Novel pyridine derivatives

ABSTRACT

wherein A and R1 to R4 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a mammal, and in particular to compounds that arepreferential agonists of the Cannabinoid Receptor 2.

The invention relates in particular to a compound of formula (I)

wherein

-   -   A is A1, A2, A3, A4 A5, A6, A7 or A8

-   -   R¹ is hydrogen or halogen;    -   R² is halogen, cycloalkyl, haloazetidinyl,        6-oxa-1-aza-spiro[3.3]heptyl or alkyl sulfonyl;    -   R³ is —OR⁸, pyrrolidinyl, halopyrrolidinyl, hydroxypyrrolidinyl,        morpholinyl, cycloalkylsulfonyl, alkoxyazetidinyl,        2-oxa-6-aza-spiro[3.3]heptyl or 2-oxa-7-azaspiro[3.4]heptyl;    -   R⁴ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl,        cycloalkyl, hydroxycycloalkyl, alkylcycloalkyl,        aminocarbonylcycloalkyl, phenyl, phenylalkyl, alkyloxetanyl,        azetidinyl or aminooxetanyl;    -   R⁵ is hydrogen, alkyl or alkyloxadiazolyl;    -   or R⁴ and R⁵, together with the carbon atom to which they are        attached, form cycloalkyl;    -   R⁶ is alkyl;    -   R⁷ is alkyl; and    -   R⁸ is haloalkyl, alkoxyalkyl, cycloalkylalkyl, haloalkyl,        halophenyl, oxetanyl, oxetanylalkyl, alkyloxetanylalkyl,        tetrahydrofuranyl, tetrahydrofuranylalkyl, alkyl sulfonylphenyl,        alkylpyrrolidinyl, alkylpyrrolidinylalkyl, azetidinyl,        morpholinylalkyl, tetrahydropyranyl, pyrrolidinylalkyl,        piperidinyl, piperidinylalkyl, alkylpiperidinylalkyl,        alkylpiperidinyl, dialkylaminoalkyl, pyridinylalkyl,        halooxetanylalkyl, dialkyloxazolylalkyl, alkyloxazolylalkyl,        halopyridinylalkyl or morpholinyl;

or a pharmaceutically acceptable salt or ester thereof.

The compound of formula (I) is particularly useful in the treatment orprophylaxis of e.g. pain, atherosclerosis, age-related maculardegeneration, diabetic retinopathy, glaucoma, retinal vein occlusion,retinopathy of prematurity, ocular ischemic syndrome, geographicatrophy, diabetes mellitus, inflammation, inflammatory bowel disease,ischemia-reperfusion injury, acute liver failure, liver fibrosis, lungfibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection,chronic allograft nephropathy, diabetic nephropathy,glomerulonephropathy, cardiomyopathy, heart failure, myocardialischemia, myocardial infarction, systemic sclerosis, thermal injury,burning, hypertrophic scars, keloids, gingivitis pyrexia, livercirrhosis or tumors, regulation of bone mass, amyotrophic lateralsclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease,stroke, transient ischemic attack or uveitis.

The compound of formula (I) is in particular useful in the treatment orprophylaxis of diabetic retinopathy, retinal vein occlusion or uveitis.

The cannabinoid receptors are a class of cell membrane receptorsbelonging to the G protein-coupled receptor superfamily. There arecurrently two known subtypes, termed Cannabinoid Receptor 1 (CB1) andCannabinoid Receptor 2 (CB2). The CB1 receptor is mainly expressed inthe central nervous (i.e. amygdala cerebellum, hippocampus) system andto a lesser amount in the periphery. CB2, which is encoded by the CNR2gene, is mostly expressed peripherally, on cells of the immune system,such as macrophages and T-cells (Ashton, J. C. et al. CurrNeuropharmacol 2007, 5(2), 73-80; Miller, A. M. et al. Br J Pharmacol2008, 153(2), 299-308; Centonze, D., et al. Curr Pharm Des 2008, 14(23),2370-42), and in the gastrointestinal system (Wright, K. L. et al. Br JPharmacol 2008, 153(2), 263-70). The CB2 receptor is also widelydistributed in the brain where it is found primarily on microglia andnot neurons (Cabral, G. A. et al. Br J Pharmacol 2008, 153(2): 240-51).

The interest in CB2 receptor agonists has been steadily on the riseduring the last decade (currently 30-40 patent applications/year) due tothe fact that several of the early compounds have been shown to havebeneficial effects in pre-clinical models for a number of human diseasesincluding chronic pain (Beltramo, M. Mini Rev Med Chem 2009, 9(1),11-25), atherosclerosis (Mach, F. et al. J Neuroendocrinol 2008, 20Suppl 1, 53-7), regulation of bone mass (Bab, I. et al. Br J Pharmacol2008, 153(2), 182-8), neuroinflammation (Cabral, G. A. et al. J LeukocBiol 2005, 78(6), 1192-7), ischemia/reperfusion injury (Pacher, P. etal. Br J Pharmacol 2008, 153(2), 252-62), systemic fibrosis(Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36;Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6),liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), 742-55;Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475-83).

Ischemia/reperfusion (FR) injury is the principal cause of tissue damageoccurring in conditions such as stroke, myocardial infarction,cardiopulmonary bypass and other vascular surgeries, and organtransplantation, as well as a major mechanism of end-organ damagecomplicating the course of circulatory shock of various etiologies. Allthese conditions are characterized by a disruption of normal bloodsupply resulting in an insufficient tissue oxygenation. Re-oxygenatione.g., reperfusion is the ultimate treatment to restore normal tissueoxygenation. However the absence of oxygen and nutrients from bloodcreates a condition in which the restoration of circulation results infurther tissue damage. The damage of reperfusion injury is due in partto the inflammatory response of damaged tissues. White blood cells,carried to the area by the newly returning blood, release a host ofinflammatory factors such as interleukins as well as free radicals inresponse to tissue damage. The restored blood flow reintroduces oxygenwithin cells that damages cellular proteins, DNA, and the plasmamembrane.

Remote ischemic preconditioning (RIPC) represents a strategy forharnessing the body's endogenous protective capabilities against theinjury incurred by ischemia and reperfusion. It describes the intriguingphenomenon in which transient non-lethal ischemia and reperfusion of oneorgan or tissue confers resistance to a subsequent episode of “lethal”ischemia reperfusion injury in a remote organ or tissue. The actualmechanism through which transient ischemia and reperfusion of an organor tissue confers protection is currently unknown although severalhypotheses have been proposed.

The humoral hypothesis proposes that the endogenous substance (such asadenosine, bradykinin, opioids, CGRP, endocannabinoids, Angiotensin I orsome other as yet unidentified humoral factor) generated in the remoteorgan or tissue enters the blood stream and activates its respectivereceptor in the target tissue and thereby recruiting the variousintracellular pathways of cardioprotection implicated in ischemicpreconditioning.

Recent data indicates that endocannabinnoids and their receptors, inparticular CB2 might be involved in pre-conditioning and contribute toprevent reperfusion injury by downregulation of the inflammatoryresponse (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62).Specifically, recent studies using CB2 tool agonists demonstrated theefficacy of this concept for reducing the FR injury in the heart (Defer,N. et al. Faseb J 2009, 23(7), 2120-30), the brain (Zhang, M. et al. JCereb Blood Flow Metab 2007, 27(7), 1387-96), the liver (Batkai, S. etal. Faseb J 2007, 21(8), 1788-800) and the kidney (Feizi, A. et al. ExpToxicol Pathol 2008, 60(4-5), 405-10).

Moreover, over the last few years, a growing body of literatureindicates that CB2 can also be of interest in sub-chronic and chronicsetting. Specific upregulation of CB1 and CB2 has been shown to beassociated in animal models of chronic diseases associated with fibrosis(Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6;Yang, Y. Y. et al. Liver Int 2009, 29(5), 678-85) with a relevantexpression of CB2 in myofibroblasts, the cells responsible for fibrosisprogression.

Activation of CB2 receptor by selective CB2 agonist has in fact beenshown to exert anti-fibrotic effect in diffuse systemic sclerosis(Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6)and CB2 receptor has emerged as a critical target in experimental dermalfibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36)and in liver pathophysiology, including fibrogenesis associated withchronic liver diseases (Lotersztajn, S. et al. Gastroenterol Clin Biol2007, 31(3), 255-8; Mallat, A. et al. Expert Opin Ther Targets 2007,11(3), 403-9; Lotersztajn, S. et al. Br J Pharmacol 2008, 153(2),286-9).

The compounds of the invention bind to and modulate the CB2 receptor andhave lower CB1 receptor activity.

In the present description the term “alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 8carbon atoms, particularly a straight or branched-chain alkyl group with1 to 6 carbon atoms and more particularly a straight or branched-chainalkyl group with 1 to 4 carbon atoms. Examples of straight-chain andbranched-chain C₁-C₈ alkyl groups are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls,the isomeric heptyls and the isomeric octyls, particularly methyl,ethyl, propyl, butyl and pentyl more particularly methyl, ethyl, propyl,isopropyl, isobutyl, tert.-butyl and isopentyl. Particular examples ofalkyl are methyl, ethyl, isopropyl, isobutyl and tert.-butyl, inparticular methyl, ethyl and tert.-butyl.

The term “cycloalkyl”, alone or in combination, signifies a cycloalkylring with 3 to 8 carbon atoms and particularly a cycloalkyl ring with 3to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. Particularexamples of “cycloalkyl” are cyclopropyl, cyclopentyl and cyclohexyl, inparticular cyclopropyl and cyclohexyl.

The term “alkoxy”, alone or in combination, signifies a group of theformula alkyl-O— in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy and tert-butoxy. Particular “alkoxy” are methoxy,ethoxy and butoxy, and in particular methoxy and butoxy.

The term “oxy”, alone or in combination, signifies the —O— group.

The terms “halogen” or “halo”, alone or in combination, signifiesfluorine, chlorine, bromine or iodine and particularly fluorine,chlorine or bromine, more particularly fluorine and chlorine. The term“halo”, in combination with another group, denotes the substitution ofsaid group with at least one halogen, particularly substituted with oneto five halogens, particularly one to four halogens, i.e. one, two,three or four halogens. A particular “halogen” is fluorine.

The term “haloalkyl”, alone or in combination, denotes an alkyl groupsubstituted with at least one halogen, particularly substituted with oneto five halogens, particularly one to three halogens. Particular“haloalkyl” are trifluoroethyl, trifluoromethyl, trifluoropropyl anddifluoroethyl, more particularly trifluoroethyl and difluoroethyl.

A particular “halophenyl” is fluorophenyl. A particular haloazetidinylis difluoroazetidinyl, in particular 3,3-difluoro-azetidin-1-yl. Aparticular halopyrrolidinyl is difluoropyrrolidinyl, in particular3,3-difluoro-pyrrolidin-1-yl, or tetrafluoropyrrolidinyl, in particular3,3,4,4-tetrafluoropyrrolidin-1-yl. A particular halooxetanyl isfluorooxetanyl. A particular halopyridinyl is fluoropyridinyl.

The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the—OH group.

The term “carbonyl”, alone or in combination, signifies the —C(O)—group.

The term “amino”, alone or in combination, signifies the primary aminogroup (—NH₂), the secondary amino group (—NH—), or the tertiary aminogroup (—N—).

The term “sulfonyl”, alone or in combination, signifies the —S(O)₂—group.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,particularly hydrochloric acid, and organic acids such as acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene sulfonic acid, salicylic acid, N-acetylcystein.In addition these salts may be prepared form addition of an inorganicbase or an organic base to the free acid. Salts derived from aninorganic base include, but are not limited to, the sodium, potassium,lithium, ammonium, calcium, magnesium salts. Salts derived from organicbases include, but are not limited to salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine,piperidine, polyamine resins. The compound of formula (I) can also bepresent in the form of zwitterions. Particularly preferredpharmaceutically acceptable salts of compounds of formula (I) are thesalts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid and methanesulfonic acid.

“Pharmaceutically acceptable esters” means that the compound of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of the compoundof general formula (I), similar to the metabolically labile esters,which are capable of producing the parent compound of general formula(I) in vivo, are within the scope of this invention.

If one of the starting materials or compounds of formula (I) contain oneor more functional groups which are not stable or are reactive under thereaction conditions of one or more reaction steps, appropriateprotecting groups (as described e.g. in “Protective Groups in OrganicChemistry” by T. W. Greene and P. G. M. Wuts, 3^(rd) Ed., 1999, Wiley,New York) can be introduced before the critical step applying methodswell known in the art. Such protecting groups can be removed at a laterstage of the synthesis using standard methods described in theliterature. Examples of protecting groups are tert-butoxycarbonyl (Boc),9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate(Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

The compound of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, mixtures ofdiastereoisomers, diastereoisomeric racemates or mixtures ofdiastereoisomeric racemates.

The term “asymmetric carbon atom” means a carbon atom with fourdifferent substituents. According to the Cahn-Ingold-Prelog Conventionan asymmetric carbon atom can be of the “R” or “S” configuration.

The invention relates in particular to:

A compound of formula (I) wherein A is A1 or A2;

A compound of formula (I) wherein R¹ is hydrogen or chloro;

A compound of formula (I) wherein R¹ is hydrogen;

A compound of formula (I) wherein R² is cycloalkyl, bishalo-azetidinylor alkylsulphonyl;

A compound of formula (I) wherein R² is cycloalkyl;

A compound of formula (I) wherein R² is cyclopropyl;

A compound of formula (I) wherein R³ is —OR⁸ or pyrrolidinyl;

A compound of formula (I) wherein R³ is —OR⁸;

A compound of formula (I) wherein R⁴ is alkyl;

A compound of formula (I) wherein R⁴ is butyl, in particulartert.-butyl;

A compound of formula (I) wherein R⁵ is hydrogen, ethyl ormethyloxadiazolyl, or R⁴ and R⁵, together with the carbon atom to whichthey are attached, form cyclohexyl;

A compound of formula (I) wherein R⁶ is methyl;

A compound of formula (I) wherein R⁷ is methyl or isopropyl;

A compound of formula (I) wherein R⁸ is haloalkyl, alkoxyalkyl,cycloalkylalkyl, haloalkyl, halophenyl, oxetanyl, oxetanylalkyl,alkyloxetanylalkyl, tetrahydrofuranyl, tetrahydrofuranylalkyl,alkylsulfonylphenyl, alkylpyrrolidinyl, alkylpyrrolidinylalkyl,azetidinyl, morpholinylalkyl, tetrahydropyranyl, pyrrolidinylalkyl,piperidinyl, piperidinylalkyl, alkylpiperidinylalkyl, alkylpiperidinyl,dialkylaminoalkyl, pyridinylalkyl, halooxetanylalkyl,dialkyloxazolylalkyl or alkyloxazolylalkyl;

A compound of formula (I) wherein R⁸ is haloalkyl, alkoxyalkyl,halophenyl, alkyl sulphonyl, sulphonylphenyl, alkylpyrrolidinyl,alkoxyalkylpyrrolidinyl, 2-oxa-6-aza-spiro[3.3]heptanyl,alkyloxetanylalkyl, oxetanylalkyl, tetrahydrofuranyl,tetrahydrofuranylalkyl, tetrahydropyranyl or alkyloxadiazolyl;

A compound of formula (I) wherein R⁸ is haloalkyl, alkoxyalkyl,halophenyl, alkyloxetanylalkyl, oxetanylalkyl, tetrahydrofuranyl,tetrahydrofuranylalkyl or tetrahydropyranyl;

A compound of formula (I) wherein R⁸ is trifluoromethyl, ethoxyethyl,methoxybutyl, fluorophenyl, oxetanylmethyl, methyloxetanylmethyl,tetrahydrofuranyl, tetrahydrofuranylmethyl or tetrahydropyranyl;

A compound of formula (I) wherein R⁸ is haloalkyl, alkoxyalkyl,halophenyl, alkyloxetanylalkyl, oxetanylalkyl, tetrahydrofuranyl,tetrahydrofuranylalkyl, tetrahydropyranyl, halopyridinylalkyl ormorpholinyl; and

A compound of formula (I) wherein R⁸ is trifluoromethyl, ethoxyethyl,methoxybutyl, fluorophenyl, oxetanylmethyl, methyloxetanylmethyl,tetrahydrofuranyl, tetrahydrofuranylmethyl, tetrahydropyranyl,difluoroethyl, fluoropyridinylmethyl or morpholinyl.

Particular R⁴ are methyl, ethyl, isopropyl, tert.-butyl,trifluoromethyl, cyclopropyl, cyclopentyl, methylcyclopropyl,aminocarbonylcyclopropyl, hydroxymethyl, hydroxypropyl,hydroxycyclopropyl, methoxymethyl, phenyl, phenylmethyl, methyloxetanyl,azetidinyl, methyloxetanyl and aminooxetanyl.

In the definition of R⁴, tert.-butyl is a particular butyl.

The invention further relates to a compound of formula (I) selectedfrom:

-   5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazole;-   5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-phenyl-1,2,4-oxadiazole;-   3-cyclopropyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-cyclopentyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-benzyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-tert-butyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-cyclopropyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-(trifluoromethyl)-1,2,4-oxadiazole;-   5-cyclopropyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole;-   3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(methoxymethyl)-1,2,4-oxadiazole;-   3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-ethyl-1,2,4-oxadiazole;-   3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole;-   3-cyclopropyl-5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazole;-   3-tert-butyl-5-[5-((3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   [3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]methanol;-   3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(trifluoromethyl)-1,2,4-oxadiazole;-   (4S)-4-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4,5-dihydro-1,3-oxazole;-   2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4-ethyl-4,5-dihydro-1,3-oxazole;-   2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-ene;-   1-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol;-   3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole;-   1-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide;-   2-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]propan-2-ol;-   2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole;-   3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole;-   5-(azetidin-3-yl)-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   2-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole;-   2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-ene;-   5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole;-   1-[6-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-4-(cyclopropylmethoxy)pyridin-3-yl]-6-oxa-1-azaspiro[3.3]heptane;-   3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole;-   1-[3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol;-   3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole;-   3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5,5-dimethyl-4H-1,3-oxazole;-   5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-propan-2-yl-1,2,4-oxadiazole;-   5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-methylsulfonylpyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole;-   1-[3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol;-   3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[(2    S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole;-   3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole;-   3-tert-butyl-5-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole;-   3-tert-butyl-5-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[(4-fluorophenyl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[(3-methyloxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[[(2    S)-1-methylpyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(1-methylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole-   3-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-amine;-   5-tert-butyl-3-[5-cyclopropyl-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   2-(5-tert-butyl-1H-imidazol-2-yl)-5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine;-   5-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,3-oxazole;-   2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-propan-2-yl-1H-imidazol-5-one;-   5-tert-butyl-3-[5-methylsulfonyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-ethyl-4-methyl-1H-imidazol-5-one;-   2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-(2-methylpropyl)-1H-imidazol-5-one;-   2-[5-bromo-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-propan-2-yl-1H-imidazol-5-one;-   5-tert-butyl-3-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-cyclopropyl-1,2,4-oxadiazole;-   5-cyclopropyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   1-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]pyrrolidin-3-ol;-   5-tert-butyl-3-[5-cyclopropyl-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(4-methylsulfonylphenoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   7-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]-2-oxa-7-azaspiro[3.4]octane;-   5-tert-butyl-3-[5-cyclopropyl-4-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole;-   4-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]morpholine;-   5-tert-butyl-3-(5-cyclopropyl-4-pyrrolidin-1-ylpyridin-2-yl)-1,2,4-oxadiazole;-   5-tert-butyl-3-(5-cyclopropyl-4-cyclopropylsulfonylpyridin-2-yl)-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(3-methoxyazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole;-   6-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;-   5-tert-butyl-3-[5-cyclopropyl-4-(2-ethoxyethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(1-methoxybutan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[2-[(2-methylpropan-2-yl)oxy]ethoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[1-[(2-methylpropan-2-yl)oxy]propan-2-yloxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(1-methoxypropan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(3-methoxybutoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-cyclopropyl-3-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(1-ethylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(1-propan-2-ylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(2-pyrrolidin-1-ylethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(2-piperidin-1-ylethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(1-piperidin-1-ylpropan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[(1-methylpiperidin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   2-tert-butyl-5-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,3,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(1-methylpiperidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(1-ethylpiperidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole;-   2-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxy-N,N-diethylpropan-1-amine;-   3-[[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxymethyl]morpholine;-   4-[2-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxyethyl]morpholine;-   5-tert-butyl-3-(5-cyclopropyl-4-piperidin-3-yloxypyridin-2-yl)-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[(3-fluorooxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[(2,5-dimethyl-1,3-oxazol-4-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[(5-methyl-1,2-oxazol-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(3-methylsulfonylphenoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-[2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-5H-1,3-oxazol-4-yl]-5-methyl-1,2,4-oxadiazole;-   5-tert-butyl-3-(6-chloro-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridin-2-yl)-1,2,4-oxadiazole;-   2-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,3,4-oxadiazole;-   5-tert-butyl-3-[6-chloro-5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(2-fluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;    and-   5-tert-butyl-3-[5-cyclopropyl-4-(pyridin-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole.-   The invention relates in particular to a compound of formula (I)    selected from:-   5-tert-butyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   3-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-[(3-methyloxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(2-ethoxyethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(3-methoxybutoxy)pyridin-2-yl]-1,2,4-oxadiazole;    and-   5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole.

The invention further relates in particular to a compound of formula (I)selected from

-   5-tert-butyl-3-[5-cyclopropyl-4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   5-tert-butyl-3-[5-cyclopropyl-4-(pyridin-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;-   2-tert-butyl-5-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,3,4-oxadiazole;-   3-tert-butyl-5-(5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)-1,2,4-oxadiazole;-   3-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole;    and-   3-tert-butyl-5-(5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazole.

The invention further relates in particular to a compound of formula (I)selected from

-   5-tert-butyl-3-[5-cyclopropyl-4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole;-   3-tert-butyl-5-(5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)-1,2,4-oxadiazole;    and-   3-tert-butyl-5-(5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazole.

The synthesis of the compound of formula (I) can, for example, beaccomplished according to the following schemes.

Unless otherwise specified, R² to R⁸ and A have in the following schemesthe meaning as defined above. In schemes 1 to 15, R¹ is hydrogen; inscheme 16, R¹ is halogen.

Following the procedure according to scheme 1, compound AA can be usedas starting material. AA is either commercially available, described inthe literature or can be synthesized by a person skilled in the art.

Compound AB can be prepared from AA by reaction with a suitablysubstituted alcohol as described in the claims, in the presence of abase, for example sodium hydride, with or without an inert solvent, forexample dimethylformamide, at temperatures ranging from room temperatureto the reflux temperature of the solvent (step a).

Conversion of compound AB to compound AC can be prepared by coupling asuitably substituted cycloalkyl metal species (e.g. a trifluoroborate[BF₃]⁻K⁺, a boronic acid B(OH)₂ or a boronic acid pinacol ester) (stepb), e.g. an organotrifluoroborate potassium salt in the presence of apalladium catalyst such aspalladium(II)acetate/butyl-1-adamantylphosphine and a base such ascesium carbonate in an inert solvent such as toluene at temperaturesbetween 50° C. and the boiling temperature of the solvent, or anarylboronic acid or arylboronic acid ester in the presence of a suitablecatalyst, in particular a palladium catalyst and more particularlypalladium(II)acetate/triphenylphosphine mixtures orpalladium(II)chloride-dppf (1,1′-bis(diphenylphosphino)ferrocene)complexes and a base such as triethylamine, sodium carbonate orpotassium phosphate in an inert solvent such as dimethylformamide,toluene, tetrahydrofuran, acetonitrile or dimethoxyethane.

AC can be selectively halogenated on position 2 to give AD for exampleby treatment of N,N-dimethylethanolamine with butyl lithium on ACfollowed by addition of a source of Bromine, e.g.1,2-dibromotetrachloroethane (step c).

Compound AE can be prepared from AD by addition of cyanide source, e.g.zinc cyanide or copper cyanide in presence of a palladium catalyst suchas palladium triphenylphosphine tetrakis ortris(dibenzylideneacetone)dipalladium(0) and dppf, in a solvent such asDMF or dioxane and refluxed to the solvent boiling point temperature(step d).

Hydrolisis of compound AE lead to the picolinic acid AF and can beperformed under acidic or basic conditions known to a person skilled inthe art, e.g. with aqueous solution of hydrochloric acid at 100° C.(step e).

Compounds of formula I with A1, can be prepared from compounds offormula AF by amide coupling methods known to a person skilled in theart, with the suitably substituted hydroxyamidine commercially availableleading to intermediate AF[Int](step f), followed by heating to cycliseto the oxadiazole ring in a high boiling point solvent such as DMF (stepg).

Compound AE can be converted to AG by treatment with hydroxylaminehydrochloride in presence of base such as triethylamine (step h).

Cylisation to compound I with A2 can be performed by amide couplingmethods known to a person skilled in the art, with the suitablysubstituted commercially available carboxylic acid to give intermediateAG[Int](step i), followed by heating to cyclise to the oxadiazole ringin a high boiling point solvent such as DMF (step j).

Alternatively, following the procedure according to scheme 2, compoundBA can be prepared from AC by oxidation with a suitable oxidizingreagent under conditions known to a person skilled in the art, e.g. bytreatment with 3-chloro perbenzoic acid in dichloromethane at ambienttemperature (step a).

Compound AE can be then prepared from BA by a cyanation method known toa person skilled in the art, such treatment withtrimethylsilanecarbonitrile followed by addition of dimethylcarbamicchloride in a solvent such as DCM.

Compound AE can be further elaborated to compounds I with A1 or A2, asdescribed in scheme 1, step e and for g and h.

Alternatively, according to scheme 3, especially when R² was asubstituent sensitive to oxidation such as groups with nitrogen,compound CA can be prepared from AB by oxidation with a suitableoxidizing reagent under conditions known to a person skilled in the art(step a), e.g. by treatment with 3-chloro perbenzoic acid indichloromethane at ambient temperature.

Compound CB can be then prepared from CA by a cyanation method known toa person skilled in the art, such treatment withtrimethylsilanecarbonitrile followed by addition of dimethylcarbamicchloride in a solvent such as DCM (step b).

Compound AE can be obtained from compound CB by substituting with anamine or salt of an amine such difluoroazetidine hydrochloride, usingBuchwald reaction conditions known to a person skilled in the art (stepc), such as Cs₂CO₃, palladium acetate and BINAP in a solvent such astoluene under reflux.

Compound AE can be further elaborated to compounds I with A1 or A2, asdescribed in scheme 1, step e and for g and h.

Alternatively, following the procedure according to scheme 4, compoundDA can be prepared from CB by treatment with hydroxylamine hydrochloridein presence of base such as triethylamine in a solvent such as DCM (stepa).

Cyclisation of compound DA to compound DB with heterocycle type A2 canbe performed by amide coupling methods known to a person skilled in theart, with the suitably substituted commercially available carboxylicacid to give intermediate DA[Int](step b), followed by heating tocyclise to the oxadiazole ring in a high boiling point solvent such asDMF (step c).

Compound I can be obtained from compound DB by substituting with anamine or salt of an amine such difluoroazetidine hydrochloride, usingBuchwald reaction conditions known to a person skilled in the art (stepd), such as Cs₂CO₃, palladium acetate and BINAP in a solvent such astoluene under reflux.

Compound AE can be further elaborated to compounds I with heterocycletype A2 by coupling R² where R² is either an alkyl chain using similarmethod as described in scheme 1 step b; or R² is an amine or thecorresponding salt using Buchwald reaction conditions as described inscheme 3 step c.

Following the procedure according to scheme 5, compound EA can be usedas starting material. EA is either commercially available, described inthe literature or can be synthesized by a person skilled in the art.

Compound EB can be obtained from compound EA (step a) by coupling withan alkyl chain using similar method as described in scheme 1 step b.

Compound EC can be prepared from EB by cyanation reaction methods, e.g.zinc cyanide or copper cyanide in presence of a palladium catalyst suchas palladium triphenylphosphine tetrakis ortris(dibenzylideneacetone)dipalladium(0) and dppf, in a solvent such asDMF or dioxane and refluxed to the solvent boiling point temperature(step b).

Compound EC can be converted to ED by treatment with hydroxylaminehydrochloride in presence of base such as triethylamine in a solventsuch as DCM (step c).

Cyclisation of compound ED to compound EE with heterocycle type A2 canbe performed by amide coupling methods known to a person skilled in theart, with the suitably substituted commercially available carboxylicacid to give intermediate ED [Int] (step d), followed by heating tocyclise to the oxadiazole ring in a high boiling point solvent such asDMF (step e).

Compound I can be obtained from compound EE (step f) by reaction with asuitably substituted alcohol as described in the claims, in the presenceof a base, for example sodium hydride, with or without an inert solvent,for example dimethylformamide, at temperatures ranging from roomtemperature to the reflux temperature of the solvent; or by reactionwith a suitably substituted amine using a base such as Cs₂CO₃ in a highboiling point solvent such as ethylene glycol or alternatively usingBuchwald reaction conditions known to a person skilled in the art, suchCs₂CO₃, palladium acetate and BINAP in a solvent such toluene underreflux.

Compound AE can be prepared from compound EC (step g) by reaction with asuitably substituted alcohol as described in the claims, in the presenceof a base, for example sodium hydride, with or without an inert solvent,for example dimethylformamide, at temperatures ranging from roomtemperature to the reflux temperature of the solvent.

Hydrolisis of compound AE lead to the picolinic acid AF and can beperformed under acidic or basic conditions known to a person skilled inthe art, e.g. with aqueous solution of hydrochloric acid at 100° C.(step h).

Compounds of formula EF can be prepared from compounds of formula AF byamide coupling methods known to a person skilled in the art, with thesuitably substituted hydrazide commercially available, in an appropriatesolvent (step i).

Cyclisation of compound EF to compound I with heterocycle type A8 can beperformed by dehydration methods (step j) known to a person skilled inthe art, e.g. treatment of compound EF by a reaction mixture oftrifluoromethanesulfonic anhydride and triphenylphosphine oxide in asolvent such as DCM.

Following the procedure according to scheme 6 (step a), compound FA canbe obtained from compound AA by coupling R² where R² is an alkyl chainusing similar method as described in scheme 1 step b.

Compound FA can be selectively carbonylated on position 2 to give FB bya method known to a person skilled in the art for example by treatmentof N,N-dimethylethanolamine with butyl lithium on AC followed byaddition of a source of carbon dioxide, e.g. dry ice (step b).

Compound FC (with A1), can be prepared from compound FB by amidecoupling methods known to a person skilled in the art, with the suitablysubstituted hydroxyamidine commercially available giving intermediate FB[Int] (step c), followed by heating to cyclise to the oxadiazole ring ina high boiling point solvent such as DMF (step d).

Compound I (with A1) can be prepared from compound FC by reaction with asuitably substituted alcohol as described in the claims, in the presenceof a base, for example sodium hydride, with or without an inert solvent,for example dimethylformamide, at temperatures ranging from roomtemperature to the reflux temperature of the solvent (step e).

Following the procedure according to scheme 7 (step a), compound GA canbe obtained from compound EA by coupling with oxetane-3-one usingGrignard reaction method known to a person skilled in the art, e.g.isopropyl magnesium chloride lithium chloride complex in a solvent suchas THF.

Compound GB can be prepared from GA by cyanation reaction methods, e.g.zinc cyanide or copper cyanide in presence of a palladium catalyst suchas palladium triphenylphosphine tetrakis ortris(dibenzylideneacetone)dipalladium(0) and dppf, in a solvent such asDMF or dioxane and refluxed to the solvent boiling point temperature(step b).

Compound GC can be prepared from GB by conversion of the hydroxy tofluorine using fluorinating reagents, such as DAST (step c).

Compound GC can be converted to GD by treatment with hydroxylaminehydrochloride in presence of base such as triethylamine in a solventsuch DCM (step d).

Cyclisation of compound GD to compound GE with heterocycle type A2 canbe performed by amide coupling methods known to a person skilled in theart, with the suitably substituted commercially available carboxylicacid giving intermediate GD[Int] (step e), followed by heating tocyclise to the oxadiazole ring in a high boiling point solvent such asDMF (step f).

Compound I (with A2) can b obtained from compound GE (step g) byreaction with a suitably substituted alcohol as described in the claims,in the presence of a base, for example sodium hydride, with or withoutan inert solvent, for example dimethylformamide, at temperatures rangingfrom room temperature to the reflux temperature of the solvent.

Following the procedure according to scheme 8, compound HA can be usedas starting material. HA is either commercially available, described inthe literature or can be synthesized by a person skilled in the art.

Compound HB can be prepared from HA by reaction with a suitablysubstituted alkyl chain with a leaving group, e.g. halogen or triflate,in the presence of a base, for example sodium hydride, in a solvent, forexample dimethylformamide, at temperatures ranging from room temperatureto the reflux temperature of the solvent (step a).

Compound HC can be prepared from HB by cyanation reaction methods knownto a person skilled in the art, e.g. zinc cyanide or copper cyanide inpresence of a palladium catalyst such as palladium triphenylphosphinetetrakis or tris(dibenzylideneacetone)dipalladium(0) and dppf, in asolvent such as DMF or dioxane and refluxed to the solvent boiling pointtemperature (step b).

Compound HC can be converted to HD by treatment with hydroxylaminehydrochloride in presence of base such as triethylamine in a solventsuch DCM (step c).

Cyclisation of compound HD to compound I, with heterocycle type A2 andR²=chlorine, can be performed by amide coupling methods known to aperson skilled in the art, with the suitably substituted commerciallyavailable carboxylic acid to give intermediate HD [Int] (step d),followed by heating to cyclise to the oxadiazole ring in a high boilingpoint solvent such as DMF (step e).

Following the procedure according to scheme 9, compound JA can beobtained from compound AF by amide coupling methods known to a personskilled in the art, with the suitably substituted amine commerciallyavailable, in an appropriate solvent such as DCM (step a).

Cyclisation of compound JA to compound I with heterocycle type A3 can beperformed by dehydration methods (step b) known to a person skilled inthe art, e.g. using a mild dehydrating reagent such as Burgess Reagentin a solvent such as THF.

Following the procedure according to scheme 10 (step a), compound KA canbe obtained from compound AF by amide coupling methods known to a personskilled in the art, with the suitably substituted amine commerciallyavailable, in an appropriate solvent such as DCM (step a).

Formation of compound KA to compound I with heterocycle type A4 can beperformed by condensation methods known to a person skilled in the art,such use of methanesulfonic acid, in a solvent such as DCM (step b).

Following the procedure according to scheme 11 (step a), compound LA canbe obtained from compound AE by amidine formation methods known to aperson skilled in the art, e.g. treatment by a reaction mixture oftrimethylaluminum on ammonium chloride in a solvent such as toluene.

Conversion of compound LA to compound I with heterocycle type A5 can beperformed by coupling method with an alpha halogeno ketone suitablysubstituted known to a person skilled in the art, e.g use of a base suchas DBU in a solvent such as ethanol giving intermediate LA[Int] (stepb), and heated to cyclise (step c).

Following the procedure according to scheme 12, compound MA can beobtained from compound AF (step a) by amide coupling methods known to aperson skilled in the art, with the suitably substituted amine, in anappropriate solvent such as THF (step a).

Conversion of compound MA to compound I with heterocycle type A6 (stepb) can be performed by cyclising using a base, e.g. potassium hydroxidein a solvent such as THF at reflux temperature of the solvent.

Following the procedure according to scheme 13 (step a), compound NA canbe obtained from compound AF by amide coupling methods known to a personskilled in the art, with the suitably substituted alpha amino alcohol,in an appropriate solvent such as DCM (step a).

Compound NB can be prepared from NA by oxidation with a suitableoxidizing reagent known to a person skilled in the art (step b), e.g. bytreatment with Dess-Martin periodinane in a solvent such as DCM.

Conversion of compound NB to compound I with heterocycle type A7 (stepc) can be performed by cyclisation method known to a person skilled inthe art, e.g. treatment with hexachloroethane and triphenylphosphine inas solvent such as acetonitrile.

Following the procedure according to scheme 14, compound OA can beobtained from compound DB by substitution with a alkylthiol, e.g.methanethiol and heated in an appropriate solvent such as DMF (step a).

Conversion to compound I can be performed by oxidation of compound OAwith a suitable oxidizing reagent under conditions known to a personskilled in the art (step b), e.g. by treatment with 3-chloro perbenzoicacid in dichloromethane at ambient temperature.

Following the procedure described in scheme 15, compound PA can beobtained from compound AF by amide coupling methods known to a personskilled in the art, with the suitably substituted amine, previouslyprepared by a skilled chemist, in an appropriate solvent such as DCM(step a).

Compound PA can be converted to compound PB (step b) by debenzylationmethods known to a person skilled in the art, e.g. treatment by BBr₃solution in DCM.

Compound PC can be prepared from compound PB by tosylation methods, e.g.4-methylbenzene-1-sulfonyl chloride with potassium carbonate in presenceof dimethylaminopyridine in a solvent such as DCM.

Compound PC can be cyclized to compound I with heterocycle type A3, byheating in a presence of a base e.g. triethylamine, in a solvent such asDMF.

Alternatively, following the procedure according to scheme 14, compoundQA can be prepared from I by oxidation with a suitable oxidizing reagentunder conditions known to a person skilled in the art, e.g. by treatmentwith 3-chloro perbenzoic acid in dichloromethane (step a).

Compound I can be prepared from QA by chlorination methods known to aperson skilled in the art, such as treatment with oxalyl chloride in asolvent such as DCM.

The invention also relates to a process for the manufacture of acompound of formula (I) as defined above comprising one of the followingsteps:

-   -   (a) the heating of a compound of formula (A)

-   -   (b) the heating of a compound of formula (B)

-   -   (c) the reaction of a compound of formula (C)

-   -   in the presence of haloazetidine or        6-oxa-1-aza-spiro[3.3]heptane, a base and a palladium catalyst;    -   (d) the reaction of a compound of formula (D)

-   -   in the presence of trifluoromethanesulfonic anhydride and        triphenylphosphine oxide;    -   (e) the reaction of a compound of formula (E1) or (E2)

-   -   in the presence of HOR, haloazetidine,        6-oxa-1-aza-spiro[3.3]heptane or HSO₂R and a base;    -   (f) the heating of a compound of formula (F)

-   -   in the presence of Burgess reagent;    -   (g) the heating of a compound of formula (G)

-   -   in the presence of methanesulfonic acid;    -   (h) the heating of a compound of formula (H)

-   -   (j) the heating of a compound of formula (J)

-   -   (k) the reaction of a compound of formula (K)

-   -   in the presence of hexachloroethane, a base and a phosphine;    -   (l) the reaction of a compound of formula (L)

-   -   in the presence of an oxidizing agent;    -   (m) the heating of a compound of formula (M)

-   -   in the presence of a base;    -   (n) the reaction of a compound of formula (N)

-   -   in the presence of a chlorinating agent and DMF; or    -   (o) the reaction of a compound of formula (C) as defined above        in the presence of HSR and a base, and then an oxidation agent;    -   wherein A, A1 to A8 and R¹ to R⁴ are as defined above and        wherein R is alkyl.

Step (a) is for example carried out at 120° C.

Step (b) is for example carried out at 130° C.

Step (c) is for example carried out at 130° C.

Step (d) is carried out for example at room temperature.

In step (e), the base is for example sodium hydride.

The Burgess reagent is commonly known to the person skilled in the art,and is methyl N-(triethylammoniumsulfonyl)carbamate.

Step (g) is for example carried out at 40° C.

Step (h) is for example carried out at 120° C.

Step (j) is for example carried out at 70° C.

In step (k), the base is for example triethylamine. The phosphine is forexample triphenylphosphine.

Step (l) can be performed with 3-chloro perbenzoic acid, e.g. indichloromethane, in particular at ambient temperature.

Step (m) is for example carried out at 80° C., for example in DMF. Thebase of step (m) is for example triethylamine.

The chlorinating agent is for example oxalyl chloride.

The invention also relates in particular to:

The use of a compound of formula (I) for the treatment or prophylaxis ofpain, atherosclerosis, age-related macular degeneration, diabeticretinopathy, glaucoma, retinal vein occlusion, retinopathy ofprematurity, ocular ischemic syndrome, geographic atrophy, diabetesmellitus, inflammation, inflammatory bowel disease, ischemia-reperfusioninjury, acute liver failure, liver fibrosis, lung fibrosis, kidneyfibrosis, systemic fibrosis, acute allograft rejection, chronicallograft nephropathy, diabetic nephropathy, glomerulonephropathy,cardiomyopathy, heart failure, myocardial ischemia, myocardialinfarction, systemic sclerosis, thermal injury, burning, hypertrophicscars, keloids, gingivitis pyrexia, liver cirrhosis or tumors,regulation of bone mass, amyotrophic lateral sclerosis, multiplesclerosis, Alzheimer's disease, Parkinson's disease, stroke, transientischemic attack or uveitis;

The use of a compound according of formula (I) for the preparation of amedicament for the treatment or prophylaxis of pain, atherosclerosis,age-related macular degeneration, diabetic retinopathy, glaucoma,retinal vein occlusion, retinopathy of prematurity, ocular ischemicsyndrome, geographic atrophy, diabetes mellitus, inflammation,inflammatory bowel disease, ischemia-reperfusion injury, acute liverfailure, liver fibrosis, lung fibrosis, kidney fibrosis, systemicfibrosis, acute allograft rejection, chronic allograft nephropathy,diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heartfailure, myocardial ischemia, myocardial infarction, systemic sclerosis,thermal injury, burning, hypertrophic scars, keloids, gingivitispyrexia, liver cirrhosis or tumors, regulation of bone mass, amyotrophiclateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, stroke, transient ischemic attack or uveitis;

A compound of formula (I) for the treatment or prophylaxis of pain,atherosclerosis, age-related macular degeneration, diabetic retinopathy,glaucoma, retinal vein occlusion, retinopathy of prematurity, ocularischemic syndrome, geographic atrophy, diabetes mellitus, inflammation,inflammatory bowel disease, ischemia-reperfusion injury, acute liverfailure, liver fibrosis, lung fibrosis, kidney fibrosis, systemicfibrosis, acute allograft rejection, chronic allograft nephropathy,diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heartfailure, myocardial ischemia, myocardial infarction, systemic sclerosis,thermal injury, burning, hypertrophic scars, keloids, gingivitispyrexia, liver cirrhosis or tumors, regulation of bone mass, amyotrophiclateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, stroke, transient ischemic attack or uveitis; and

A method for the treatment or prophylaxis of pain, atherosclerosis,age-related macular degeneration, diabetic retinopathy, glaucoma,retinal vein occlusion, retinopathy of prematurity, ocular ischemicsyndrome, geographic atrophy, diabetes mellitus, inflammation,inflammatory bowel disease, ischemia-reperfusion injury, acute liverfailure, liver fibrosis, lung fibrosis, kidney fibrosis, systemicfibrosis, acute allograft rejection, chronic allograft nephropathy,diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heartfailure, myocardial ischemia, myocardial infarction, systemic sclerosis,thermal injury, burning, hypertrophic scars, keloids, gingivitispyrexia, liver cirrhosis or tumors, regulation of bone mass, amyotrophiclateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson'sdisease, stroke, transient ischemic attack or uveitis, which methodcomprises administering an effective amount of a compound of formula (I)to a patient in need thereof.

The invention particularly relates to a compound of formula (I) for thetreatment or prophylaxis of ischemia, reperfusion injury, liver fibrosisor kidney fibrosis, in particular ischemia or reperfusion injury.

The invention particularly relates to a compound of formula (I) for thetreatment or prophylaxis of myocardial infarction.

The invention further particularly relates to a compound of formula (I)for the treatment or prophylaxis of age-related macular degeneration,diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy ofprematurity, ocular ischemic syndrome, geographic atrophy or uveitis.

The invention further particularly relates to a compound of formula (I)for the treatment or prophylaxis of amyotrophic lateral sclerosis ormultiple sclerosis.

The invention is further directed to a compound of formula (I), whenmanufactured according to a process according to the invention.

Another embodiment of the invention provides a pharmaceuticalcomposition or medicament containing a compound of the invention and atherapeutically inert carrier, diluent or excipient, as well as a methodof using the compounds of the invention to prepare such composition andmedicament. In one example, the compound of formula (I) may beformulated by mixing at ambient temperature at the appropriate pH, andat the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of formula (I) is formulated inan acetate buffer, at pH 5. In another embodiment, the compound offormula (I) is sterile. The compound may be stored, for example, as asolid or amorphous composition, as a lyophilized formulation or as anaqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Formsand Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound of the present invention or pharmaceutical composition thereof)or aid in the manufacturing of the pharmaceutical product (i.e.,medicament).

The invention will now be illustrated by the following examples whichhave no limiting character.

EXAMPLES

Abbreviations

MPLC=medium pressure liquid chromatography, model Combiflash Companionfrom TELEDYNE ISCO; MS=mass spectrometry; ESI=electrospray;BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;CDI=1,1′-carbonyldiimidazole; Cs₂CO₃=cesium carbonate;DCM=dichloromethane; DIPEA=N-ethyl-N-isopropylpropan-2-amine;DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene; DMF=dimethylformamide;DMSO=dimethyl-sulfoxide; dppf=1,1′-bis(diphenylphosphino)ferrocene;EtOH=ethanol;HATU=2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V);HBTU=O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate;HPLC=LC=high performance liquid chromatography;m-CPBA=meta-chloroperoxybenzoic acid; MeOH=methanol; NaHCO₃=sodiumhydrogenocarbonate; Na₂SO₄=sodium sulfate; Pd(OAc)₂=palladium(II)acetate; RT=room temperature;TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-tetrafluoroborate;TBME=methyl tert-butylether, THF=tetrahydrofuran; TFA=trifluoroaceticacid; TLC=thin layer chromatography; TMS-CN=Trimethylsilyl cyanide.

Example 15-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazolea) 3-bromo-4-(cyclopropylmethoxy)pyridine

To a solution of 3-bromo-4-chloropyridine (CAS 36953-42-1) (8 g, 41.6mmol, Eq: 1.00) in dry DMF (100 mL) under argon atmosphere at RT wasadded cyclopropylmethanol (CAS 2516-33-8) (3.15 g, 3.45 mL, 43.6 mmol,Eq: 1.05) and by portions NaH (1.75 g, 43.6 mmol, Eq: 1.05). Theresulting reaction was stirred at RT until gas evolution stopped. Thereaction mixture was then stirred at 100° C. for 3 h and controlled byTLC. The reaction was cooled down to RT, quenched by addition of waterand the mixture concentrated in vacuo. The residue was redissolved inethyl acetate, extracted with aqueous NaHCO₃ 1M, the organic phase driedover Na₂SO₄, filtered and evaporated down to dryness. Flashchromatography with a 120 g SiO₂ column, with an eluent mixture ofheptane and ethyl acetate to give 8.25 g of light yellow oil (Yield:87%). MS (ESI, m/z): 228.2 (M).

b) 3-cyclopropyl-4-(cyclopropylmethoxy)pyridine

To a solution of 3-bromo-4-(cyclopropylmethoxy)pyridine (8.1 g, 35.5mmol, Eq: 1.00) in a mixture of toluene (150 mL) and water (18 mL) wasadded potassium cyclopropyltrifluoroborate (CAS 1065010-87-8) (5.52 g,37.3 mmol, Eq: 1.05), Cs₂CO₃ (23.1 g, 71.0 mmol, Eq: 2.0),butyldi-1-adamantylphosphine (382 mg, 1.07 mmol, Eq: 0.03) and Pd(OAc)₂(159 mg, 710 μmol, Eq: 0.02). The reaction mixture was stirred at 125°C. for 7 h. Reaction mixture was cooled down and poured into aseparatory funnel, ethyl acetate and water were added. After extractionof the mixture, the organic phase was collected, dried over Na₂SO₄ andevaporated down to dryness. Flash chromatography with a 120 g SiO₂column, and an eluent mixture of heptane and ethyl acetate gave 4.6 g ofthe desired product (Yield 68%). MS (ESI, m/z): 190.3 (MH⁺).

c) 2-bromo-5-cyclopropyl-4-(cyclopropylmethoxy)pyridine

To a solution of N,N-dimethylethanolamine (1.13 g, 1.28 mL, 12.7 mmol,Eq: 3.0) in hexane (9 mL) under an argon atmosphere at −15° C. wasslowly added BuLi 1.6M in hexane (15.9 mL, 25.4 mmol, Eq: 6.0) and thereaction mixture was stirred at −15° C. for 15 min. Addition of3-cyclopropyl-4-(cyclopropylmethoxy)pyridine (0.8 g, 4.23 mmol, Eq:1.00) in dry toluene (5 mL) to the reaction at −15° C. was followed bystirring at −15° C. for 1 h. Reaction was then cooled down to −78° C.and a solution of 1,2-dibromotetrachloroethane (4.13 g, 12.7 mmol, Eq:3.0) in dry toluene (6 mL) was added. The resulting white suspension wasthen stirred for 1 h at −78° C. and controlled by LC-MS. The reactionwas then quenched with water, allowed to warm up to RT and diluted withethyl acetate. The mixture was poured into a separatory funnel,extracted with aqueous NaHCO₃ 1M. The organic phase was dried overNa₂SO₄ and evaporated down to dryness. Flash chromatography with a 70 gSiO₂ column, and an eluent mixture of heptane and ethyl acetate gave 980mg of colorless oil (Yield 77%). MS (ESI, m/z): 268.1 (M).

d) 5-cyclopropyl-4-(cyclopropylmethoxy)picolinonitrile

To a solution of 2-bromo-5-cyclopropyl-4-(cyclopropylmethoxy)pyridine(1.15 g, 3.65 mmol, Eq: 1.00) in Dioxane (25 mL) under an argonatmosphere was added copper (I) cyanide (1.31 g, 14.6 mmol, Eq: 4.0),tetraethylammonium cyanide (570 mg, 3.65 mmol, Eq: 1.00), dppf (323 mg,583 μmol, Eq: 0.16) and Pd₂(dba)₃ (134 mg, 146 μmol, Eq: 0.04). Theresulting reaction mixture was stirred at 110° C. for 4 h. Reactionmixture was filtered over a pad of Celite, and the filtrate was pouredinto a separatory funnel. After dilution with ethyl acetate, extractionwith aqueous NaHCO₃ 1M, the organic phase was collected, dried andevaporated down to dryness. Flash chromatography with a 50 g SiO₂column, and an eluent mixture of heptane and ethyl acetate gave 392 mgof the desired product (Yield 50%). MS (ESI, m/z): 215.3 (MH⁺).

e) 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic Acid

To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)picolinonitrile(200 mg, 933 μmol, Eq: 1.00) in water (4 mL) was added potassiumhydroxide (786 mg, 14.0 mmol, Eq: 15.0). The reaction was stirred at110° C. overnight and monitored by TLC. KOH was neutralized using HClaqueous solution and the pH was adjusted to 1-2. Afterwards anextraction with DCM/MeOH (4:1) was made and the organic phase wascollected, dried and the solvent evaporated. The crude material waspurified by MPLC ISCO on SiO₂ column giving 200 mg of compound as awhite powder (Yield 92%). MS (ESI, m/z): 234.6 (MH⁺).

f)5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazole

In a micro-wave vial with DMF (1.5 mL),5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid (46.7 mg, 200 μmol,Eq: 1.00) was combined with CDI (32.4 mg, 200 μmol, Eq: 1.0). Thereaction mixture was stirred for 30 min at room temperature under Argon.N′-hydroxyacetimidamide (CAS 22059-22-9) (14.8 mg, 200 μmol, Eq: 1.0)was added. The reaction mixture was stirred for 1 h, and then heated to130° C. with microwave for another 1 h. The reaction was controlled byLC-MS which showed complete conversion. The reaction mixture wasdirectly purified by preparative HPLC without any work-up. MS (ESI,m/z): 272.5 (MH+).

Example 25-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-phenyl-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 1f, using5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid andN′-hydroxybenzimidamide (CAS 613-92-3) as starting materials, anddirectly purified by preparative HPLC without any work-up. MS (ESI,m/z): 334.5 (MH+).

Example 33-cyclopropyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 1f, using5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid andN′-hydroxycyclopropanecarboximidamide (CAS 51285-13-3) as startingmaterials, and directly purified by preparative HPLC without anywork-up. MS (ESI, m/z): 298.5 (MH+).

Example 43-cyclopentyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 1f, using5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid andN′-hydroxycyclopentanecarboximidamide (CAS 99623-12-8) as startingmaterials, and directly purified by preparative HPLC without anywork-up. MS (ESI, m/z): 326.3 (MH+).

Example 53-benzyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 1f, using5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid andN′-hydroxy-2-phenylacetimidamide (CAS 19227-11-3) as starting materials,and directly purified by preparative HPLC without any work-up. MS (ESI,m/z): 348.2 (MH+).

Example 63-tert-butyl-5-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 1f, using5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid andN′-hydroxypivalimidamide (CAS 42956-75-2) as starting materials, anddirectly purified by preparative HPLC without any work-up. MS (ESI,m/z): 314.2 (MH+).

Example 73-cyclopropyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazolea) 3-bromo-4-(2,2,2-trifluoroethoxy)pyridine

To a solution of 3-bromo-4-chloropyridine (CAS 36953-42-1) (25 g, 130mmol, Eq: 1.00) in DMF (333 mL) was added 2,2,2-trifluoroethanol (CAS75-89-8) (19.5 g, 195 mmol, Eq: 1.5) and potassium tert-butoxide (21.9g, 195 mmol, Eq: 1.5). The reaction was stirred overnight at 110° C. Thesolvent was partially evaporated and partitioned between NaHCO₃ aqueoussaturated solution and ethyl acetate. The organic layer was dried overNa₂SO₄ and evaporated. Product used as a crude (85% yield). MS (ESI,m/z): 257.3 (MH+).

b) 3-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine

To a solution of 3-bromo-4-(2,2,2-trifluoroethoxy)pyridine (28.44 g,88.9 mmol, Eq: 1.00) in a mixture of toluene (275 mL) and water (32.5mL) was added potassium cyclopropyltrifluoroborate (CAS 1065010-87-8)(14.5 g, 97.8 mmol, Eq: 1.1), palladium (II) acetate (798 mg, 3.55 mmol,Eq: 0.04), butyldi-1-Adamantylphosphine (1.27 g, 3.55 mmol, Eq: 0.04)and Cs₂CO₃ (72.4 g, 222 mmol, Eq: 2.5) under an argon atmosphere. Thereaction mixture was stirred over night at 115° C. and controlled byTLC. The reaction mixture was extracted with ethyl acetate and water.The organic phase was dried over Na₂SO₄ and evaporated down to dryness.The crude material was purified by MPLC ISCO on SiO₂ column with agradient heptane in ethyl acetate giving yellow viscous oil (Yield 72%).MS (ESI, m/z): 218.5 (MH+).

c) 3-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide

To a solution of 3-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine (13.89g, 64 mmol, Eq: 1.00) in DCM (355 mL) was added m-CPBA (16.6 g, 95.9mmol, Eq: 1.5). Reaction was stirred overnight at RT. Extraction withNaHCO₃ saturated aqueous solution and DCM. Organic layer was dried onNa₂SO₄ and evaporated. Column on SiO₂ using MPLC ISCO with a gradientDCM/MeOH (Yield 68%). MS (ESI, m/z): 234.5 (MH+).

d) 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinonitrile

3-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide (10.20 g, 43.7mmol, Eq: 1.00) was dissolved in DCM (163 mL).Trimethylsilanecarbonitrile (CAS 7677-24-9) (5.64 g, 7.11 mL, 56.9 mmol,Eq: 1.3) was then added dropwise followed by dimethylcarbamic chloride(7.06 g, 6.03 mL, 65.6 mmol, Eq: 1.5). The reaction mixture was stirredat room temperature over night. Saturated aqueous NaHCO₃ (20 mL) wasadded with stirring. The reaction mixture was poured into DCM andextracted with H₂O. The organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on SiO₂ using MPLC ISCO with a gradient heptane in ethylacetate (Yield 64%). MS (ESI, m/z): 243.5 (MH+).

e) 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid

5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinonitrile (6.87 g, 28.4mmol, Eq: 1.00) was dissolved in HCl 25% aqueous sol (170 mL, 1.4 mol,Eq: 50.0). Reaction was heated at 110° C. After 3 h reaction wascomplete. Reaction was cooled down to RT. HCl was neutralized using 6MNaOH aqueous solution followed by NaOH pellets. Then the pH was adjustedto 1-2 with HCl 2M. The precipitate formed was filtered off to givetitle compound (Yield 99%). MS (ESI, m/z): 262.5 (MH+).

f)3-cyclopropyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid(50 mg, 191 μmol, Eq: 1.00) in dry DMF (1.5 mL) was added CDI (34.1 mg,211 μmol, Eq: 1.1) and reaction stirred for 30 min at RTN′-hydroxycyclopropanecarboximidamide (CAS 51285-13-3) (211 μmol, Eq:1.1) was added, stirred for 1 h at RT and after that overnight at 120°C. The reaction mixture was controlled by LC-MS. The reaction wasdirectly purified by preparative HPLC without any further work-up. MS(ESI, m/z): 326 (MH+).

Example 85-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-(trifluoromethyl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 7f, using5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid and2,2,2-trifluoro-N′-hydroxyacetimidamide (CAS 4314-35-6) as startingmaterials, and directly purified by preparative HPLC without any furtherwork-up. MS (ESI, m/z): 354 (MH+).

Example 95-cyclopropyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazolea) 5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide

To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)picolinonitrile(synthesis described previously as Example 1d) (390 mg, 1.82 mmol, Eq:1.00) in EtOH (4 mL) was added hydroxylamine hydrochloride (126 mg, 1.82mmol, Eq: 1.00) and triethylamine (184 mg, 254 μL, 1.82 mmol, Eq: 1.00).The reaction mixture was stirred at 70° C. for 4 h and controlled byLC-MS which showed complete conversion to the desired product. Thereaction mixture was diluted with ethyl acetate, poured into aseparatory funnel, washed with water, and the organic phase dried overNa₂SO₄ and evaporated down to dryness. Flash chromatography with a 20 gSiO₂ column, eluent mixture of DCM and MeOH gave 418 mg of the desiredproduct (Yield 88%). MS (ESI, m/z): 248.2 (MH+).

b)5-cyclopropyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of cyclopropanecarboxylic acid (CAS 1759-53-1) (179 μmol,Eq: 1.05) in dry DMF (1.0 mL) was added CDI (28.9 mg, 179 μmol, Eq:1.05) and the resulting reaction mixture was stirred at RT for 45 min,followed by addition of5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide (42.0mg, 170 μmol, Eq: 1.00). The reaction was then stirred at RT for 2 h andcontrolled by LC-MS which showed complete consumption of the startingmaterial to produce the intermediate. The reaction was then heated at130° C. in a micro-wave for 45 min, controlled by LC-MS. The reactionwas directly purified by preparative HPLC without any work-up. MS (ESI,m/z): 298.4 (MH+).

Example 105-tert-butyl-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 9b, usingpivalic acid (CAS 75-98-9) and5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide asstarting materials, and directly purified by preparative HPLC withoutany work-up. MS (ESI, m/z): 354 (MH+).

Example 112-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazolea)5-cyclopropyl-4-(cyclopropylmethoxy)-N-(3-(hydroxymethyl)pentan-3-yl)picolinamide

To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid(previously described as Example 1e) (50 mg, 0.214 mmol, Eq: 1.00) inDCM (2 mL) was added4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloridehydrate (CAS 3945-69-5) (69.5 mg, 0.236 mmol, Eq: 1.1). The reaction wasstirred 30 min at RT. Then 2-amino-2-ethylbutan-1-ol (27.6 mg, 0.236mmol, Eq: 1.1) (CAS 39884-49-6) was added and the reaction stirred at RTovernight. LC-MS showed reaction was complete. Extraction with NaHCO₃saturated aqueous solution and columning on SiO₂ with a gradientheptane/ethyl acetate gave 30 mg of the title compound (Yield 42%). MS(ESI, m/z): 333.3 (MH+).

b)2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole

To a solution of5-cyclopropyl-4-(cyclopropylmethoxy)-N-(3-(hydroxymethyl)pentan-3-yl)picolinamide(34 mg, 102 μmol, Eq: 1.00) (carefully dried) in dry THF was addedBurgess reagent (25.6 mg, 107 μmol, Eq: 1.05). Reaction was stirred atRT under argon overnight. LC-MS showed reaction was complete.Evaporation of the solvent and extraction with NaHCO₃ saturated aqueoussolution and ethyl acetate. Organic layer was dried on Na₂SO₄ andevaporated. Column on SiO₂ with a gradient heptane/ethyl acetate (Yield62%). MS (ESI, m/z): 315.2 (MH+).

Example 123-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(methoxymethyl)-1,2,4-oxadiazole

The title compound was synthesized in a similar manner as Example 9b,using 5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamidewith potassium carbonate (Eq: 1.0) and 2-methoxyacetyl chloride (CAS38870-89-2) as starting materials and, directly purified by preparativeHPLC without any work-up. MS (ESI, m/z): 302.3 (MH+).

Example 133-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-ethyl-1,2,4-oxadiazole

The title compound was synthesized in a similar manner as Example 9b,using 5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamidewith potassium carbonate (Eq: 1.0) and propionyl chloride (CAS 79-03-8)as starting materials, and directly purified by preparative HPLC withoutany work-up. MS (ESI, m/z): 286.2 (MH+).

Example 143-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole

The title compound was synthesized in a similar manner as Example 9b,using 5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamidewith potassium carbonate (Eq: 1.0) and isobutyryl chloride (CAS 79-30-1)as starting materials, and directly purified by preparative HPLC withoutany work-up. MS (ESI, m/z): 300.3 (MH+).

Example 153-cyclopropyl-5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazolea) 3-bromo-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide

To a solution of 3-bromo-4-(2,2,2-trifluoroethoxy)pyridine (previouslydescribed as Example 7a) (21 g, 67.3 mmol, Eq: 1.00) in DCM (400 mL) wasadded by portions m-CPBA (19.6 g, 87.4 mmol, Eq: 1.3). The reactionmixture was then stirred over the week-end at RT and monitored by LC-MS.Reaction mixture was poured into a separatory funnel and extracted withaqueous NaHCO₃ 1M. Aqueous phase was back-extracted with a mixture ofethyl acetate and organic phases were combined, dried over Na₂SO₄ andevaporated down to dryness. Flash chromatography with a 330 g SiO₂column, eluent mixture of DCM and MeOH giving 16.2 g of the desiredproduct (Yield 88%). MS (ESI, m/z): 272.3 (M).

b) 5-bromo-4-(2,2,2-trifluoroethoxy)picolinonitrile

3-bromo-4-(2,2,2-trifluoroethoxy)pyridine 1-oxide (21.5 g, 79 mmol, Eq:1.00) was combined with DCM (344 mL). Trimethylsilanecarbonitrile (11.8g, 14.8 mL, 119 mmol, Eq: 1.5) was then added dropwise followed bydimethylcarbamic chloride (12.7 g, 10.9 mL, 119 mmol, Eq: 1.5). Thereaction mixture was stirred at room temperature over night. Saturatedaqueous NaHCO₃ (20 mL) was added with stirring. The reaction mixture waspoured into DCM and extracted with H₂O. The organic layers were driedover Na₂SO₄ and concentrated in vacuo. The crude material was purifiedby flash chromatography on SiO₂ using MPLC ISCO with a eluent gradientof heptane/ethyl acetate (Yield 27%). MS (ESI, m/z): 281.3 (M).

c)5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrile

To a solution of 5-bromo-4-(2,2,2-trifluoroethoxy)picolinonitrile (587mg, 2.09 mmol, Eq: 1.00) in dry toluene (10.4 mL) in a schlenk tube wasadded 3,3-difluoroazetidine hydrochloride (CAS 288315-03-7) (298 mg, 2.3mmol, Eq: 1.1), Cs₂CO₃ (1.36 g, 4.18 mmol, Eq: 2.0), Pd(OAc)₂ (46.9 mg,209 μmol, Eq: 0.1) and BINAP (130 mg, 209 μmol, Eq: 0.1). The reactionmixture was heated to 120° C. and stirred for 1 h. Reaction mixturefiltered over a pad of Celite, diluted with ethyl acetate, organic phaseextracted with aqueous saturated NaHCO₃, dried over Na₂SO₄ andevaporated down to dryness. The crude material was purified by flashchromatography (SiO₂, 50 g, gradient ethyl acetate in heptane) giving480 mg (Yield 78%) of the desired compound. MS (ESI, m/z): 294.2 (MH+).

d) 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinic Acid

To a solution of5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrile(680 mg, 2.32 mmol, Eq: 1.00) in EtOH (7.73 mL) in a schlenk tube wasadded KOH 4M aqueous solution (651 mg, 11.6 mmol, Eq: 5.0). The reactionmixture was heated to 105° C. and stirred for 2 h. The reaction mixturewas poured in a separatory funnel with a mixture of ethyl acetate andHCl 6.9M (2.69 mL, 18.6 mmol, Eq: 8.0) and water, extraction, theorganic phase were collected, dried over Na₂SO₄ and evaporated down togive 397 mg of the desired product as an off-white solid (Yield 54%). MS(ESI, m/z): 311.2 (MH−).

e)3-cyclopropyl-5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

In a 5 mL sealed vial,5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinic acid(100 mg, 320 μmol, Eq: 1.00) and CDI (54.5 mg, 336 μmol, Eq: 1.05) werecombined with DMF (1.5 mL). The reaction mixture was stirred at roomtemp for 30 min. N′-hydroxycyclopropanecarboximidamide (CAS 51285-13-3)(336 μmol, Eq: 1.05) was added and the mixture was stirred at room tempfor 1 h. The reaction mixture was then heated to 120° C. for 4 h. Thereaction mixture was poured into EtOAc and extracted with saturatedNaHCO₃ aqueous solution. The organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (SiO₂, 10 g, with a gradient ethyl acetate in heptane) togive 33.6 mg of the title compound (Yield 27%). MS (ESI, m/z): 377.4(MH+).

Example 165-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 15e, using5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinic acidand N′-hydroxyacetimidamide (CAS 22059-22-9) as starting materials, anddirectly purified by flash chromatography (SiO₂, 10 g, gradient ethylacetate in heptane) giving 26 mg of desired compound (Yield 23%). MS(ESI, m/z): 351.2 (MH+).

Example 173-tert-butyl-5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 15e, using5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinic acidand N′-hydroxypivalimidamide (CAS 42956-75-2) as starting materials, anddirectly purified by flash chromatography (SiO₂, 10 g, gradient ethylacetate in heptane giving 55 mg of desired compound (Yield 44%). MS(ESI, m/z): 393.3 (MH+).

Example 18[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]methanol

The title compound was synthesized in a similar manner as Example 9b,using 5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamidewith potassium carbonate (Eq: 1.00) and 2-methoxyacetyl chloride (CAS38870-89-2) as starting materials and after microwave heating wasfollowed by addition of NaOH 4M aqueous solution (Eq: 1.5) Reaction wasstirred overnight at 80° C. and directly purified by preparative HPLCwithout any work-up. MS (ESI, m/z): 288.1 (MH+).

Example 193-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(trifluoromethyl)-1,2,4-oxadiazole

The title compound was synthesized in a similar manner as Example 9b,using 5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamidewith triethylamine (Eq: 1.1) and 2,2,2-trifluoroacetic anhydride (CAS407-25-0) as starting materials in DCM and heated at 70° C. withmicrowave. Solvent was removed in vacuo, residue redissolved in DMF anddirectly purified by preparative HPLC to give the desired compound. MS(ESI, m/z): 326.2 (MH+).

Example 20(4S)-4-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4,5-dihydro-1,3-oxazole

The title compound was synthesized in analogy to Example 11, using5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid (previously describedas Example 1e) and (S)-2-amino-3,3-dimethylbutan-1-ol (CAS 112245-13-3)as starting materials for the first step. MS (ESI, m/z): 315.2 (MH+).

Example 212-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4-ethyl-4,5-dihydro-1,3-oxazole

The title compound was synthesized in analogy to Example 11, using5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid (previously describedas Example 1e) and 2-aminobutan-1-ol (CAS 96-20-8) as starting materialsfor the first step. MS (ESI, m/z): 287.2 (MH+).

Example 222-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-ene

The title compound was synthesized in analogy to Example 11, using5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid (previously describedas Example 1e) and (1-aminocyclohexyl)methanol (CAS 4313-56-8) asstarting materials for the first step. MS (ESI, m/z): 327.3 (MH+).

Example 231-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol

The title compound was synthesized in analogy to Example 9b, using1-hydroxycyclopropanecarboxylic acid (CAS 17994-25-1) and5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide asstarting materials, and directly purified by preparative HPLC withoutany work-up. MS (ESI, m/z): 314.0 (MH+).

Example 243-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 9b, using1-methylcyclopropanecarboxylic acid (CAS 6914-76-7) and5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide asstarting materials, and directly purified by preparative HPLC withoutany work-up. MS (ESI, m/z): 312.1 (MH+).

Example 251-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboxamide

The title compound was synthesized in analogy to Example 9b, using1-carbamoylcyclopropanecarboxylic acid (CAS 6914-74-5) and5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide asstarting materials, and directly purified by preparative HPLC withoutany work-up. MS (ESI, m/z): 341.1 (MH+).

Example 262-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]propan-2-ol

The title compound was synthesized in analogy to Example 9b, using2-hydroxy-2-methylpropanoic acid (CAS 594-61-6) and5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide asstarting materials, and directly purified by preparative HPLC withoutany work-up. MS (ESI, m/z): 316.2 (MH+).

Example 272-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole

The title compound was synthesized in analogy to Example 11, using5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (previouslydescribed as Example 7e) and 2-amino-2-ethylbutan-1-ol (CAS 39884-49-6)as starting materials for the first step. MS (ESI, m/z): 343.2 (MH+).

Example 283-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 9b, using3-methyloxetane-3-carboxylic acid (CAS 28562-68-7) and5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide asstarting materials, and directly purified by preparative HPLC withoutany work-up. MS (ESI, m/z): 328.3 (MH+).

Example 295-(azetidin-3-yl)-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 9b, using1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (CAS 142253-55-2) and5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide asstarting materials followed by deprotection of the Boc group byevaporation of the DMF, crude redissolved in TFA. The reaction wasstirred at RT for 30 min, volatiles were removed in vacuo and residuewas redissolved in ethyl acetate. Organic phase was extracted withaqueous NaOH 1M, dried over Na₂SO₄ and evaporated down to dryness. Crudewas purified by preparative HPLC. MS (ESI, m/z): 313.1 (MH+).

Example 302-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole

The title compound was synthesized in a similar manner as Example 11,using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinicacid (previously described as Example 15d) and 2-amino-2-ethylbutan-1-ol(CAS 39884-49-6) as starting materials for the first step. MS (ESI,m/z): 394.0 (MH+).

Example 312-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-ene

The title compound was synthesized in analogy to Example 11, using5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (previouslydescribed as Example 7e) and (1-aminocyclohexyl)methanol (CAS 4313-56-8)as starting materials for the first step. MS (ESI, m/z): 355.5 (MH+).

Example 325-tert-butyl-3-[4-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazolea) 3-bromo-4-(cyclopropylmethoxy)pyridine 1-oxide

In a 250 mL pear-shaped flask, 3-bromo-4-(cyclopropylmethoxy)pyridine,previously described as Example 1a, (3.7 g, 16.2 mmol, Eq: 1.00) wascombined with DCM (81.1 mL) to give a colorless solution. m-CPBA (5.45g, 24.3 mmol, Eq: 1.5) was added. The reaction mixture was stirred atroom temperature for 2 h. The reaction mixture was poured into 250 mLDCM and extracted with 1M NaHCO₃. The organic layers were dried overNa₂SO₄ and concentrated in vacuo. The crude material was purified byflash chromatography (SiO₂, 120 g, gradient MeOH in DCM) giving 3.39 gof the title compound as a white solid (Yield 85%). MS (ESI, m/z): 244.2(M).

b) 5-bromo-4-(cyclopropylmethoxy)picolinonitrile

To a solution of 3-bromo-4-(cyclopropylmethoxy)pyridine 1-oxide (9.5 g,38.9 mmol, Eq: 1.00) in dry DCM (160 mL) cooled down to 0° C. and underargon atmosphere was slowly added TMS-CN (5.79 g, 7.83 mL, 58.4 mmol,Eq: 1.5) followed by addition of dimethylcarbamoyl chloride (6.28 g,5.37 mL, 58.4 mmol, Eq: 1.5). The reaction mixture was then stirred atRT overnight and monitored by LC-MS which showed complete consumption ofthe starting material. Addition of aqueous Na₂CO₃ 2M solution andmixture was stirred for 10 min, then poured into a separatory funnel,addition of water and extraction. Organic phase collected, dried overNa₂SO₄ and evaporated down to dryness. Flash chromatography with a 120 gSiO₂ column, eluent mixture of heptane and ethyl acetate giving 3.52 gof the desired isomer (Yield 36%). MS (ESI, m/z): 253.4 (M).

c) 5-bromo-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide

To a solution of 5-bromo-4-(cyclopropylmethoxy)picolinonitrile (0.75 g,2.96 mmol, Eq: 1.00) in EtOH (8 mL) was added hydroxylaminehydrochloride (309 mg, 4.44 mmol, Eq: 1.5) and triethylamine (450 mg,620 μL, 4.44 mmol, Eq: 1.5). The reaction mixture was then stirred at70° C. for 45 min under microwave radiation and reaction monitored byTLC (eluent: ethyl acetate). Reaction mixture was poured into aseparatory funnel, diluted with ethyl acetate, extracted with aqueousNaHCO₃ 1M. Organic phase dried over Na₂SO₄ and evaporated down todryness. Flash chromatography with a 50 g SiO₂ column, eluent mixture ofheptane and ethyl acetate giving 482 mg of the desired product (Yield57%). MS (ESI, m/z): 286.3 (M).

d)3-(5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)-5-tert-butyl-1,2,4-oxadiazole

To a solution of5-bromo-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide (2.1 g, 7.34mmol, Eq: 1.00) in dry DMF (25 mL) under argon atmosphere at 0° C. wasadded potassium carbonate (1.12 g, 8.07 mmol, Eq: 1.1) followed by slowaddition of pivaloyl chloride (CAS 3282-30-2) (929 mg, 948 μL, 7.71mmol, Eq: 1.05). The resulting reaction was stirred for 15 min at 0° C.and then stirred for 30 min at RT, reaction was monitored by LC-MS. Thereaction was then stirred at 130° C. under microwave radiation for 30min and controlled by LC-MS which showed complete conversion to thedesired product. Removal of DMF in vacuo, residue redissolved in ethylacetate and solution was poured into a separatory funnel. Extractionwith aqueous NaHCO₃ 1M, organic phase dried over Na₂SO₄ and evaporateddown to dryness. Flash chromatography with a 70 g SiO₂ column, eluentmixture of heptane and ethyl acetate giving 2.4 g of the desired product(Yield 93%). MS (ESI, m/z): 352.4 (M).

e)5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of3-(5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)-5-tert-butyl-1,2,4-oxadiazole(0.06 g, 170 μmol, Eq: 1.00) in dry toluene (1 mL) under argonatmosphere was added 3,3-difluoroazetidine hydrochloride (CAS288315-03-7) (24.3 mg, 187 μmol, Eq: 1.1), Pd(OAc)₂ (3.82 mg, 17.0 μmol,Eq: 0.1), BINAP (10.6 mg, 17.0 μmol, Eq: 0.1) and Cs₂CO₃ (111 mg, 341Eq: 2.0). The reaction mixture was stirred at 130° C. for 60 min undermicrowave radiation and monitored by LC-MS. The reaction mixture wasfiltered over a pad of Celite, filtrate was evaporated down anddissolved in 1 mL DMSO. Purification was done by preparative HPLCwithout any prior work-up. MS (ESI, m/z): 365.5 (MH+).

Example 335-tert-butyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazolea) 5-cyclopropyl-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide

To a solution of 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinonitrile,previously described as Example 7d, (1.62 g, 6.69 mmol, Eq: 1.00) inEtOH (13.0 mL) the following was added hydroxylamine hydrochloride (465mg, 6.69 mmol, Eq: 1.0) and triethylamine (677 mg, 932 μL, 6.69 mmol,Eq: 1.0). The reaction was stirred for 3 h at 70° C. and monitored withLC-MS. Another 0.5 Eq. of Hydroxylamine hydrochloride (232 mg) andtriethylamine (465 μL) were added as complete conversion had not takenplace. The reaction was stirred for a further 3 h at 70° C. The reactionmixture was poured into a separating funnel, ethyl acetate was added andthe mixture was extracted with aqueous NaHCO₃ 1M. The organic phase wasdried over Na₂SO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography on SiO₂, 20 g, gradient ethyl acetatein heptane giving 650 mg of the title compound as a white powder (yield35%). MS (ESI, m/z): 276.5 (MH+).

b)5-tert-butyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of5-cyclopropyl-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide(0.080 g, 291 μmol, Eq: 1.00) in dry DMF (1.29 mL) under argonatmosphere was added K₂CO₃ (40.2 mg, 291 μmol, Eq: 1.0) followed bypivaloyl chloride (CAS 3282-30-2) (35.0 mg, 35.8 μL, 291 μmol, Eq: 1.0).The reaction was stirred at RT for 45 min and controlled by LC-MS whichshowed complete conversion to the intermediate. The reaction mixture wasstirred overnight at 120° C. and controlled by LC-MS which showedcomplete conversion to the desired product. The reaction mixture wasdiluted with ethyl acetate, poured into a separatory funnel andextracted with water. The organic phase was dried over Na₂SO₄ andevaporated down to dryness. The crude material was purified by flashchromatography (SiO₂, 10 g, gradient ethyl acetate in heptane) giving 55mg of the title compound as a light yellow waxy solid (Yield 55%). MS(ESI, m/z): 342.5 (MH+).

Example 343-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 9b, using1-methylcyclopropanecarboxylic acid (CAS 6914-76-7) and5-cyclopropyl-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide,described as Example 33a, as starting materials, and directly purifiedby preparative HPLC without any work-up. MS (ESI, m/z): 340.4 (MH+).

Example 351-[6-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-4-(cyclopropylmethoxy)pyridin-3-yl]-6-oxa-1-azaspiro[3.3]heptane

The title compound was synthesized in analogy to Example 32e, using3-(5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)-5-tert-butyl-1,2,4-oxadiazoleand 6-oxa-1-azaspiro[3.3]heptane hemioxalate (CAS 1359655-43-8) asstarting materials, and purified by preparative HPLC. MS (ESI, m/z):371.4 (MH+).

Example 363-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 33b, using5-cyclopropyl-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide andisobutyryl chloride (CAS 79-30-1) as starting materials, and purified bypurified by flash chromatography. MS (ESI, m/z): 328.1 (MH+).

Example 371-[3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol

The title compound was synthesized in analogy to Example 9b, using1-hydroxycyclopropanecarboxylic acid (CAS 17994-25-1) and5-cyclopropyl-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide(described as Example 33a) as starting materials, and directly purifiedby preparative HPLC without any work-up. MS (ESI, m/z): 342.1 (MH+).

Example 383-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 9b, using3-methyloxetane-3-carboxylic acid (CAS 28562-68-7) and5-cyclopropyl-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide(described as Example 33a) as starting materials, and purified bypurified by flash chromatography. MS (ESI, m/z): 356.5 (MH+).

Example 393-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

5-cyclopropyl-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide,described as Example 33a, (60 mg, 218 μmol, Eq: 1.00) was combined withDCM (2.6 mL) and treated with triethyl orthoformate (129 mg, 145 μL, 872μmol, Eq: 4.0) under Nitrogen. The resulting solution was then treatedwith boron trifluoride etherate (3.09 mg, 2.76 μL, 21.8 μmol, Eq: 0.1)and allowed to stir for 2 h at RT. 0.5 more equivalents of triethylorthoformate (16.1 mg) and 0.1 equivalents of boron trifluoride etherate(0.773 mg) were added and the mixture left to stir overnight. Themixture was brought up to a basic pH with NaHCO₃ and extracted with DCM.The aqueous layer was then extracted with ethyl acetate two times. Theorganic layers were combined, dried and concentrated in vacuo. The crudematerial was purified by flash chromatography (SiO₂, 10 g, gradientethyl acetate in heptane) giving 48 mg of the title compound as a whitesolid (Yield 77%). MS (ESI, m/z): 286.4 (MH+).

Example 403-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 7f, using5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid andN′-hydroxypivalimidamide (CAS 42956-75-2) as starting materials, anddirectly purified by preparative HPLC without any work-up. MS (ESI,m/z): 342.5 (MH+).

Example 412-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5,5-dimethyl-4H-1,3-oxazole

The title compound was synthesized in a similar manner as Example 11,using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (previouslydescribed as Example 7e) and 1-amino-2-methylpropan-2-ol (CAS 2854-16-2)as starting materials for the first step. The second step differs asfollow: To a solution of5-cyclopropyl-N-(2-hydroxy-2-methylpropyl)-4-(2,2,2-trifluoroethoxy)picolinamide(60 mg, 0.181 mmol, Eq: 1.00) in DCM (900 μL) was added methanesulfonicacid (59 μL, 0.9 mmol, Eq: 5.0). Reaction was heated at 40° C. 2 h.LC-MS showed reaction was complete. Extraction with DCM/NaHCO₃ saturatedaqueous solution Organic layer was dried on MgSO₄ and evaporated. Columnon SiO₂ with a gradient heptane/ethyl acetate. MS (ESI, m/z): 315.5(MH+) to give 5.9 mg of the title compound as colorless viscous oil.

Example 425-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-propan-2-yl-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 7f, using5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid andN′-hydroxyisobutyrimidamide (CAS 35613-84-4) as starting materials, anddirectly purified by preparative HPLC without any work-up. MS (ESI,m/z): 328.4 (MH+).

Example 435-tert-butyl-3-[4-(cyclopropylmethoxy)-5-methylsulfonylpyridin-2-yl]-1,2,4-oxadiazolea)5-tert-butyl-3-(4-(cyclopropylmethoxy)-5-(methylthio)pyridin-2-yl)-1,2,4-oxadiazole

To a solution of3-(5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)-5-tert-butyl-1,2,4-oxadiazole,previously described as Example 32d, (0.08 g, 227 μmol, Eq: 1.00) in dryDMF (1.5 mL) under argon atmosphere was added methanethiol, sodium salt(CAS 5188-07-8) (19.4 mg, 273 μmol, Eq: 1.2) and the resulting reactionmixture was stirred at 100° C. overnight and controlled by TLC. Reactionmixture poured into a separatory funnel, dilution with ethlycetate,extraction with aqueous NaHCO₃ 1M. The aqueous phase was back-extractedwith ethyl acetate, organic phase combined, dried over Na₂SO₄ andevaporated down to dryness. Flash chromatography with a 10 g SiO₂column, eluent mixture of heptane and ethyl acetate gave 49 mg of thedesired product (Yield 67%). MS (ESI, m/z): 319.9 (MH+).

b)5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-methylsulfonylpyridin-2-yl]-1,2,4-oxadiazole

To a solution of5-tert-butyl-3-(4-(cyclopropylmethoxy)-5-(methylthio)pyridin-2-yl)-1,2,4-oxadiazole(0.045 g, 141 μmol, Eq: 1.00) in DCM (1 mL) was added m-CPBA (63.1 mg,282 μmol, Eq: 2.0). The reaction mixture was stirred at RT overnight andcontrolled by LC-MS. Only partial conversion to the sulfone and no morestarting material but major product is the sulfoxide. Addition of m-CPBA(12.2 mg, 70.4 μmol, Eq: 0.5) to the reaction mixture was stirred at RTfor 2 h, control by LC-MS showed change in conversion but not total. Thereaction was stopped anyway. Evaporation of the volatiles and residuewas redissolved in DMSO for purification by preparative HPLC without anywork-up giving 18.3 mg of the desired product (Yield 37%). MS (ESI,m/z): 352.5 (MH+).

Example 445-tert-butyl-3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazolea)5-(3,3-difluoroazetidin-1-yl)-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide

To a solution of5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrile,previously described as Example 15c, (1 g, 3.41 mmol, Eq: 1.00) in EtOH(16.6 mL) was added hydroxylamine hydrochloride (261 mg, 156 μL, 3.75mmol, Eq: 1.1) and triethylamine (380 mg, 524 μL, 3.75 mmol, Eq: 1.1).The reaction mixture was heated up to 70° C. and left for half an hour.LC-MS showed the reaction was complete. The reaction mixture was pouredinto a separatory funnel, ethyl acetate was added and the mixture wasextracted with aqueous saturated NaHCO₃ 1M. The organic phase was driedover Na₂SO₄ and evaporated down to dryness to give 1.09 g of the desiredcompound as a white powder (yield 98%). MS (ESI, m/z): 327.2 (MH+).

b)5-tert-butyl-3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of5-(3,3-difluoroazetidin-1-yl)-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide(0.08 g, 245 μmol, Eq: 1.00) in dry DMF (1.09 mL) under argon atmospherewas added K₂CO₃ (37.3 mg, 270 μmol, Eq: 1.1) followed by pivaloylchloride (CAS 3282-30-2) (32.5 mg, 33.2 μL, 270 μmol, Eq: 1.1). Thereaction was stirred at RT for 45 min and controlled by LC-MS whichshowed complete conversion to the intermediate. The reaction mixture wasstirred overnight at 120° C. and controlled by LC-MS which showedcomplete conversion to the desired product. The reaction mixture wasdiluted with ethyl acetate, poured into a separatory funnel andextracted with water. The organic phase was dried over Na₂SO₄ andevaporated down to dryness. The crude material was purified by flashchromatography (SiO₂, gradient ethyl acetate in heptane) giving 44 mg ofthe title compound as a white powder (Yield 45%). MS (ESI, m/z): 393.1(MH+).

Example 453-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 44b, using5-(3,3-difluoroazetidin-1-yl)-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamideand isobutyryl chloride (CAS 79-30-1) as starting materials, andpurified by purified by flash chromatography. MS (ESI, m/z): 379.1(MH+).

Example 461-[3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol

To a solution of 1-hydroxycyclopropanecarboxylic acid (CAS 17994-25-1)(27.5 mg, 270 μmol, Eq: 1.1) in DMF (1.44 mL) was added CDI (43.7 mg,270 μmol, Eq: 1.1) and the resulting reaction mixture was stirred at RTfor 45 min, followed by the addition of5-(3,3-difluoroazetidin-1-yl)-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide,previously described as Example 44a, (80 mg, 245 μmol, Eq: 1.00). Thereaction was then stirred at RT for 2 h and monitored by LC-MS whichshowed complete consumption of the starting material to form theintermediate. The reaction mixture was then heated to 130° C. and leftto stir overnight. The reaction was diluted with ethyl acetate andextracted with water. The organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (SiO₂, 10 g, gradient ethyl acetate in heptane) giving41.7 mg of the title compound as a white powder (Yield 43%). MS (ESI,m/z): 393.4 (MH+).

Example 473-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 46, using3-methyloxetane-3-carboxylic acid (CAS 28562-68-7) and5-(3,3-difluoroazetidin-1-yl)-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamideas starting materials, and purified by purified by flash chromatography.MS (ESI, m/z): 407.5 (MH+).

Example 485-tert-butyl-3-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazolea) 2,4-dichloro-5-cyclopropylpyridine

To a solution of 5-bromo-2,4-dichloropyridine (CAS 849937-96-8) (22.95g, 96.1 mmol, Eq: 1.00) in Toluene (352 mL) and Water (48.0 mL) wasadded Pd(OAc)₂ (431 mg, 1.92 mmol, Eq: 0.02),butyldi-1-adamantylphosphine (1.03 g, 2.88 mmol, Eq: 0.03), potassiumcyclopropyltrifluoroborate (CAS 1065010-87-8) (14.9 g, 101 mmol, Eq:1.05) and Cs₂CO₃ (62.6 g, 192 mmol, Eq: 2.0). The resulting reactionmixture was stirred at 110° C. overnight and controlled by TLC. Thereaction was found to be only partially complete so 0.5 more equivalents(7.5 g) of potassium cyclopropyltrifluororate were added (3 times).Reaction mixture concentrated in vacuo then diluted with ethyl acetateand the solution poured into a separatory funnel. Extraction withaqueous saturated NaHCO₃, organic phase dried over NaSO₄ and evaporateddown to dryness. Flash chromatography with a 330 g SiO₂ column, eluentmixture of heptane and ethyl acetate giving 7.39 g of the desiredproduct (Yield 40%). MS (ESI, m/z): 188.2 (M).

b) 4-chloro-5-cyclopropylpicolinonitrile

To a solution of 2,4-dichloro-5-cyclopropylpyridine (7.35 g, 39.1 mmol,Eq: 1.00) dissolved in dry DMF (130 mL), dppf (1.73 g, 3.13 mmol, Eq:0.08) was added followed by dicyanozinc (2.75 g, 23.5 mmol, Eq: 0.6) andPd₂dba₃ (1.95 mmol, Eq: 0.05). Reaction was stirred at 100° C. for 2 h,controlled by TLC. Reaction mixture filtered on a pad of Celite,filtrate diluted with ethyl acetate, extraction with water, aqueousphase back-extracted with ethyl acetate, organic phase dried over Na₂SO₄and concentrated in vacuo. Purification with a 330 g SiO₂ column, eluentmixture of Heptane and EtOAc giving 6.82 g of the title compound as ayellow solid (Yield 97%). MS (ESI, m/z): 179.2 (MH+).

c) 4-chloro-5-cyclopropyl-N′-hydroxypicolinimidamide

To a solution of 4-chloro-5-cyclopropylpicolinonitrile (3.2 g, 17.9mmol, Eq: 1.00) in EtOH (120 mL) was added hydroxylamine hydrochloride(1.87 g, 26.9 mmol, Eq: 1.5) and triethylamine (5 mL, 35.8 mmol, Eq:2.0). The reaction was heated at 90° C. and monitored with LC-MS. Thereaction mixture was poured into a separating funnel, diluted with DCMand the mixture extracted with aqueous NaHCO₃ saturated solution. Theorganic phase was dried over Na₂SO₄ and concentrated in vacuo to give awhite crystalline solid (Yield 96%). MS (ESI, m/z): 212.5 (MH+).

d) 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole

To a solution of 4-chloro-5-cyclopropyl-N′-hydroxypicolinimidamide (3.64g, 17.2 mmol, Eq: 1.00) in dry DMF (115 mL) was added pivaloyl chloride(CAS 3282-30-2) (2.7 g, 2.75 mL, 22.4 mmol, Eq: 1.3) and triethylamine(4.79 mL, 34.4 mmol, Eq: 2.0). The reaction was stirred at RT 30 min.LC-MS showed formation of the intermediate. Reaction mixture was thenheated at 110° C. overnight. Solvent was partially evaporated the crudeextracted with ethyl acetate and NaHCO₃ aqueous saturated solution.Organic layer was dried on Na₂SO₄ and evaporated. Column on SiO₂ columnusing MPLC ISCO with a gradient ethyl acetate in heptane gave the titleproduct as yellow viscous oil (Yield 77%). MS (ESI, m/z): 278.6 (MH+).

e)5-tert-butyl-3-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

To a solution of 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole (0.05 g, 180 μmol, Eq: 1.00) in dry DMF(1.5 mL) was added (S)-1,1,1-trifluoropropan-2-ol (CAS 3539-97-7) (30.8mg, 270 μmol, Eq: 1.5) followed by NaH (10.8 mg, 270 μmol, Eq: 1.5). Thereaction mixture was stirred at RT for 15 min, then stirred undermicrowave radiation for 30 min at 100° C. and monitored by LC-MS. Thereaction mixture was quenched with water and directly purified bypreparative HPLC without any work-up giving 44.2 mg of the desiredproduct (Yield 69%). MS (ESI, m/z): 356.5 (MH+).

Example 495-tert-butyl-3-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(R)-1,1,1-trifluoropropan-2-ol (75% in TBME) (CAS 17628-73-8) asstarting materials, and purified by preparative HPLC without anywork-up. MS (ESI, m/z): 356.5 (MH+).

Example 503-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 46, using1-methylcyclopropanecarboxylic acid (CAS 6914-76-7) and5-(3,3-difluoroazetidin-1-yl)-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamideas starting materials, and purified by purified by flash chromatography.MS (ESI, m/z): 391.1 (MH+).

Example 513-tert-butyl-5-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazolea) 4-chloro-3-cyclopropylpyridine

To a solution of 3-bromo-4-chloropyridine (7.1 g, 36.9 mmol, Eq: 1.00)in toluene/water (153 mL/18 mL) was added PotassiumCyclopropyltrifluoroborate (CAS 1065010-87-8) (8.41 g, 38.7 mmol, Eq:1.05), palladium (II) acetate (331 mg, 1.48 mmol, Eq: 0.04), cesiumcarbonate (30.1 g, 92.2 mmol, Eq: 2.5) and Butyldi-1-Adamantylphosphine(661 mg, 1.84 mmol, Eq: 0.05). Reaction was stirred at 115° C. overnightunder argon. LC-MS showed product. Extraction with water/ethyl acetate(3 times). Organic layer was dried on MgSO₄ and evaporated. Column onSiO₂ with a gradient heptane/ethyl acetate gave 3.8 g of the desiredcompound as a yellow oil (Yield 67%). MS (ESI, m/z): 154.0 (MH+).

b) 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic Acid

To a solution of N,N-Dimethylethanolamine (2.18 g, 2.46 mL, 24.4 mmol,Eq: 2.5) in Hexane at −15° C. under argon was slowly added BuLi 1.6M inHexane (30.5 mL, 48.8 mmol, Eq: 5.0). The reaction was stirred at −15°C. during 20 min. The reaction was cooled down to −78° C. beforeaddition of 4-chloro-3-cyclopropylpyridine (1.5 g, 9.77 mmol, Eq: 1.0).Reaction was stirred 1 h at −78° C. before pellets of dry ice addition.The reaction was slowly allowed to reach −20° C. LC-MS confirmed productformation. Reaction was quenched with water and stirred 5 min.Extraction with HCl 4M aqueous solution and ethyl acetate (3 times).Organic layer was dried on MgSO₄ and evaporated to give yellow oil.Diethyl ether was poured on the crude, giving a white suspension, andplaced in the fridge. Filtration and washed with ether. Mother liquorwas concentrated and again ether was added. Precipitate was filtered anddried under high vacuum giving 850 mg of title compound as white powder(Yield 44%). MS (ESI, m/z): 196.0 (MH−).

c) 3-tert-butyl-5-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole

To a solution of 4-chloro-5-cyclopropylpicolinic acid (300 mg, 1.52mmol, Eq: 1.00) in dry DMF (6 mL) was added CDI (369 mg, 2.28 mmol, Eq:1.5) and reaction stirred for 30 min at RT. N′-hydroxypivalimidamide(CAS 42956-75-2) (265 mg, 2.28 mmol, Eq: 1.5) was then added, stirredfor 1 h at RT and heated to 100° C. over night. The reaction mixture wascontrolled by LC-MS. The reaction mixture was concentrated and theresidue was dissolved in ethyl acetate. The extraction was accomplishedwith 1M NaHCO₃, dried over Na₂SO₄ and concentrated. The crude materialwas purified by flash chromatography (SiO₂, 10 g, eluent: heptane/ethylacetate) giving 100 mg of the title compound as light yellow liquid(Yield 23%). MS (ESI, m/z): 278.4 (MH+).

d)3-tert-butyl-5-[5-cyclopropyl-4-[(2R)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

To a solution of3-tert-butyl-5-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole (48mg, 173 μmol, Eq: 1.00) in dry DMF (100 mL) were added(R)-1,1,1-trifluoropropan-2-ol (84.5 mg, 518 μmol, Eq: 3.0) (CAS17628-73-8) and NaH (20.7 mg, 518 μmol, Eq: 3.0) and reaction stirred atRT for 30 min. The reaction mixture was then heated to 100° C. for 30min in the microwave. The reaction was directly purified by preparativeHPLC without any work-up giving the title compound as a white solid. MS(ESI, m/z): 356.3 (MH+).

Example 523-tert-butyl-5-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 51d, using3-tert-butyl-5-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(S)-1,1,1-trifluoropropan-2-ol (CAS 3539-97-7) as starting materials,and purified by preparative HPLC without any work-up. MS (ESI, m/z):356.4 (MH+).

Example 535-tert-butyl-3-[5-cyclopropyl-4-[(4-fluorophenyl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(4-fluorophenyl)methanol (CAS 459-56-3) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 368.6(MH+).

Example 545-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andoxetan-3-ol (CAS 7748-36-9) as starting materials, and purified bypreparative HPLC without any work-up. MS (ESI, m/z): 316.5 (MH+).

Example 555-tert-butyl-3-[5-cyclopropyl-4-[(3-methyloxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(3-methyloxetan-3-yl)methanol (CAS 3143-02-0) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 344.5(MH+).

Example 565-tert-butyl-3-[5-cyclopropyl-4-(oxolan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(tetrahydrofuran-2-yl)methanol (CAS 97-99-4) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 344.6(MH+).

Example 575-tert-butyl-3-[5-cyclopropyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(S)-(1-methylpyrrolidin-2-yl)methanol (CAS 34381-71-0) as startingmaterials, and purified by preparative HPLC without any work-up. MS(ESI, m/z): 357.2 (MH+).

Example 585-tert-butyl-3-[5-cyclopropyl-4-(oxetan-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andoxetan-2-ylmethanol (CAS 61266-70-4) as starting materials, and purifiedby preparative HPLC without any work-up. MS (ESI, m/z): 330.5 (MH+).

Example 595-tert-butyl-3-[5-cyclopropyl-4-(1-methylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-methylpyrrolidin-3-ol (CAS 13220-33-2) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 343.5(MH+).

Example 603-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-aminea)N-(3-(3-(5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl)-1,2,4-oxadiazol-5-yl)oxetan-3-yl)-2,2,2-trifluoroacetamide

The title compound was synthesized in analogy to Example 9b, using3-(2,2,2-trifluoroacetamido)oxetane-3-carboxylic acid (CAS 1392072-19-3)and 5-cyclopropyl-4-(cyclopropylmethoxy)-N′-hydroxypicolinimidamide asstarting materials. DMF was evaporated, residue redissolved in ethylacetate and poured into a separatory funnel, extraction with aqueousNaHCO₃ 1M, organic phase dried over Na₂SO₄ and evaporated down todryness. Flash chromatography with SiO₂ column, eluent mixture ofheptane and ethyl acetate. MS (ESI, m/z): 425.2 (MH+).

b)3-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-amine

To a solution ofN-(3-(3-(5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl)-1,2,4-oxadiazol-5-yl)oxetan-3-yl)-2,2,2-trifluoroacetamide(0.06 g, 141 μmol, Eq: 1.00) in ammonia 7N in MeOH (1.01 mL, 7.07 mmol,Eq: 50.0) was stirred at 100° C. for 30 min under microwave radiationand reaction was monitored by LC-MS. When the reaction was completed,volatiles were removed in vacuo and the residue was redissolved in DMF.Purification was done by preparative HPLC without any work-up procedureand gave 9 mg of the desired product. MS (ESI, m/z): 329.4 (MH+).

Example 615-tert-butyl-3-[5-cyclopropyl-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and4-fluorophenol (CAS 371-41-5) as starting materials, and purified bypreparative HPLC without any work-up. MS (ESI, m/z): 354.5 (MH+).

Example 625-tert-butyl-3-[5-cyclopropyl-4-(oxolan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andtetrahydrofuran-3-ol (CAS 453-20-3) as starting materials, and purifiedby preparative HPLC without any work-up. MS (ESI, m/z): 330.5 (MH+).

Example 635-tert-butyl-3-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andtetrahydro-2H-pyran-4-ol (CAS 2081-44-9) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 344.5(MH+).

Example 642-(5-tert-butyl-1H-imidazol-2-yl)-5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridinea)5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinimidamide

To a solution of ammonium chloride (47.4 mg, 887 μmol, Eq: 2) in toluene(0.56 mL) was added at 0° C. for 10 minutes trimethylaluminum (443 μL,887 μmol, Eq: 2.0). Reaction was then brought at RT for 20 minutes.5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinonitrile(130 mg, 443 μmol, Eq: 1.00), previously described as Example 15c,dissolved in toluene was then added and the reaction mixture heated upto 80° C. and stirred for 1 h. The reaction mixture was then cooled downto RT, quenched with water and poured into a DCM/silica slurry. This wasthen filtered and washed through with methanol to give 250 mg of ayellow solid. The crude material was purified by flash chromatography onSiO₂, 10 g, gradient methanol in DCM giving 21 mg of the title compoundas light yellow powder (Yield 15%). MS (ESI, m/z): 311.4 (MH+).

b)2-(5-tert-butyl-1H-imidazol-2-yl)-5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine

5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)picolinimidamide(20 mg, 64.5 μmol, Eq: 1.00), 1-bromo-3,3-dimethylbutan-2-one (24.2 mg,18.2 μL, 135 μmol, Eq: 2.1) and DBU (49.1 mg, 48.6 μL, 322 μmol, Eq:5.0) were combined with Ethanol (0.77 mL). The reaction mixture washeated up to 115° C. and stirred overnight. The crude material waspurified by preparative HPLC giving 5 mg of the title compound as whitepowder (Yield 19%). MS (ESI, m/z): 391.5 (MH+).

Example 655-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,3-oxazolea) 5-cyclopropyl-4-(cyclopropylmethoxy)-N-(2-hydroxy-3,3-dimethylbutyl)picolinamide

To a solution of 5-cyclopropyl-4-(cyclopropylmethoxy)picolinic acid,previously described as Example 1e, (200 mg, 0.857 mmol, Eq: 1.00) in8.5 mL DCM was added HATU (158 mg, 1.03 mmol, Eq: 1.2) and DIPEA (449μL, 2.57 mmol, Eq: 3.0). Reaction was stirred 15 min at 40° C., then1-amino-3,3-dimethylbutan-2-ol hydrochloride (158 mg, 1.03 mmol, Eq:1.2) (CAS 1438-15-9) was added. Reaction was stirred 2 h at 40° C.Extraction with DCM/NaHCO₃ saturated aqueous solution. Organic layer wasdried on sodium sulfate and evaporated. Column on SiO₂ with a gradientheptane/ethyl acetate gave 126 mg of the title compound as colorlessviscous oil (Yield 44%). MS (ESI, m/z): 333.5 (MH+).

b)5-cyclopropyl-4-(cyclopropylmethoxy)-N-(3,3-dimethyl-2-oxobutyl)picolinamide

To a solution of5-cyclopropyl-4-(cyclopropylmethoxy)-N-(2-hydroxy-3,3-dimethylbutyl)picolinamide(125 mg, 0.376 mmol, Eq: 1.00) in DCM (3.8 mL) was added Dess-Martinperiodinane (181 mg, 0.414 mmol, Eq: 1.1) and the reaction was stirredovernight at RT. LC-MS showed reaction was complete. Sodium thiosulfatesolution was added to the crude and stirred for 10 min before extractionwith NaHCO₃ saturated aqueous solution and DCM. Column on SiO₂ with agradient heptane/ethyl acetate gave 116 mg of the title compound aswhite waxy solid (Yield 93%). MS (ESI, m/z): 331.5 (MH+).

c)5-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,3-oxazole

Hexachloroethane was dissolved in anhydrous acetonitrile. Then5-cyclopropyl-4-(cyclopropylmethoxy)-N-(3,3-dimethyl-2-oxobutyl)picolinamidewas dissolved in Acetonitrile and added. The reaction mixture was cooledto 0° C. and triethylamine followed by triphenylphosphine were added.The ice bath was removed and the reaction mixture was stirred for 2hours. LC-MS showed some SM left. Another 3 Eq. hexachloroethane,triethylamine and finally triphenylphosphine were added at 0° C.Acetonitrile was evaporated and the crude extracted with DCM/brine 3times. Organic layer was dried on Na₂SO₄ and evaporated. Column on SiO₂with a gradient heptane/ethyl acetate to give 14 mg of the titlecompound (Yield 60%). MS (ESI, m/z): 313.5 (MH+).

Example 662-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-propan-2-yl-1H-imidazol-5-one

5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid, previouslydescribed as Example 7e, (100 mg, 383 μmol, Eq: 1.00) in1,2-Dichloroethane (1.91 mL) had thionyl chloride (68.3 mg, 41.9 μL, 574μmol, Eq: 1.5) added to it. The reaction mixture was heated up to 90° C.and left to reflux for 3 h. The reaction mixture was concentrated invacuo. Product was used immediately in the next step and dissolved inTHF (526 μL). A mixture of 2-amino-2,3-dimethylbutanamide (46.6 mg, 358μmol, Eq: 1.00) and triethylamine (36.2 mg, 49.8 μL, 358 μmol, Eq: 1.0)in 130 μL of tetrahydrofuran was added and the reaction stirred at 4 hat RT. The reaction mixture was poured into water, extracted with ethylacetate and the organic layers combined, dried, and concentrated invacuo to give a solid which was used immediately in the next step anddissolved in THF (536 μL). This was added to a solution of potassiumhydroxide (40.3 mg, 718 μmol, Eq: 2.0) and water (15 μL) and thereaction was refluxed for 2 hours. The mixture was poured into water andextracted with ethyl acetate. The organic layers were combined beforebeing dried on Na₂SO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography (SiO₂, 10 g, gradient ethyl acetate inheptane) giving 43 mg of the title compound as a white solid (Yield34%). MS (ESI, m/z): 356.1 (MH+).

Example 675-tert-butyl-3-[5-methylsulfonyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazolea) 2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-(methylsulfonyl)pyridin-4-ol

To a solution of5-tert-butyl-3-(4-(cyclopropylmethoxy)-5-(methylsulfonyl)pyridin-2-yl)-1,2,4-oxadiazole,described as Example 43, (330 mg, 939 μmol, Eq: 1.00) in dry DCM (5 ml)under an argon atmosphere was added BBr₃ 1M solution in DCM (1.88 mL,1.88 mmol, Eq: 2.0). The reaction mixture was stirred at RT overnightand monitored by LC-MS until complete conversion. The reaction mixturewas quenched by addition of water, stirred for 10 min and the mixturewas then poured into a separatory funnel and pH was adjusted to 7 andextracted with DCM and then ethyl acetate. All the organic layers weredried over Na₂SO₄ and evaporated down to dryness giving 140 mg of thetitle compound as white solid (Yield 50%). MS (ESI, m/z): 296.4 (MH−).

b)5-tert-butyl-3-[5-methylsulfonyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-(methylsulfonyl)pyridin-4-ol (40mg, 135 Eq: 1.00) in DMF (1 mL) was added Cs₂CO₃ (65.7 mg, 202 μmol, Eq:1.5) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS 6226-25-1)(62.4 mg, 38.8 μL, 269 μmol, Eq: 2.0). Reaction was heated at 90° C.during 1.5 h in the microwave and purified by preparative HPLC withoutany work-up. MS (ESI, m/z): 380.5 (MH+).

Example 682-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-ethyl-4-methyl-1H-imidazol-5-one

The title compound was synthesized in a similar manner as Example 66,using 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (Eq: 1.0),previously described as Example 7e, with CDI (Eq: 1.1), DIPEA (Eq: 2.2)and 1-amino-2-methyl-1-oxobutan-2-aminium chloride (CAS 18305-22-1) asstarting materials for the amide coupling step. MS (ESI, m/z): 342.1(MH+).

Example 692-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-(2-methylpropyl)-1H-imidazol-5-one

The title compound was synthesized in analogy to Example 68, using5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (Eq: 1.0),previously described as Example 7e, with CDI (Eq: 1.1), DIPEA (Eq: 2.2)and 2-amino-2,4-dimethylpentanamide (CAS 113509-60-7) as startingmaterials for the amide coupling step. MS (ESI, m/z): 370.5 (MH+).

Example 705-tert-butyl-3-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazolea) 2,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine

To a solution of 2,5-dichloropyridin-4-ol (CAS 847664-65-7) (5 g, 30.5mmol, Eq: 1.00) in DMF (51 mL) was added cesium carbonate (14.9 g, 45.7mmol, Eq: 1.5) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.59mL, 45.7 mmol, Eq: 1.5). Reaction was heated at 90° C. overnight.Reaction was filtered to remove Cs₂CO₃ (cake washed with ethyl acetate)and solvent evaporated. Extraction of the crude using ethylacetate/water. Organic layer was dried on Na₂SO₄ and evaporated. Columnon SiO₂ using MPLC Isco with a gradient heptane/ethyl acetate gave 6.64g of title compound as off-white solid (Yield 88%). MS (ESI, m/z): 246.3(MH+).

b) 5-chloro-4-(2,2,2-trifluoroethoxy)picolinonitrile

2,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine (4 g, 16.3 mmol, Eq:1.00), Dicyanozinc (2.1 g, 17.9 mmol, Eq: 1.1),1,1′-bis(diphenylphosphino)ferrocene (721 mg, 1.3 mmol, Eq: 0.08) andPd₂(dba)₃ (744 mg, 0.813 mmol, Eq: 0.05) were combined in DMF and thereaction heated at 100° C. 2 days. Evaporation of the solvent,extraction with ethyl acetate/NaHCO₃ saturated aqueous solution Organiclayer dried on sodium sulfate and evaporated. Column on SiO₂ with MPLCIsco with a gradient heptane/ethyl acetate gave 2.1 g of title compoundas white solid (Yield 54%). MS (ESI, m/z): 237.3 (MH+).

c) 5-chloro-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide

To a solution of 5-chloro-4-(2,2,2-trifluoroethoxy)picolinonitrile (200mg, 0.845 mmol, Eq: 1.00) in EtOH (5.6 mL) was added hydroxylaminehydrochloride (65 mg, 0.93 mmol, Eq: 1.1) and triethylamine (128 mg, 177μL, 1.27 mmol, Eq: 1.5). The reaction was heated with microwave 30 minat 80° C. and monitored with LC-MS. The reaction mixture was poured intoa separating funnel, DCM was added and the mixture was extracted withaqueous NaHCO₃ saturated solution. The organic phase was dried overNa₂SO₄ and concentrated in vacuo to give 223 mg of title compound aswhite powder (Yield 97%). MS (ESI, m/z): 270.4 (MH+).

d)5-tert-butyl-3-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of5-chloro-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide (0.1 g, 371μmol, Eq: 1.00) in dry DMF (2.5 mL) under argon atmosphere was addedDIPEA (130 μL, 742 μmol, Eq: 2.0) followed by pivaloyl chloride (CAS3282-30-2) (53.7 mg, 54.8 μL, 445 μmol, Eq: 1.2). The reaction wasstirred at RT for 45 min and controlled by LC-MS which showed completeconversion to the intermediate. The reaction mixture was heated withmicrowave 30 min at 120° C. and controlled by LC-MS which showedcomplete conversion to the desired product. The solvent was evaporatedand the crude diluted with ethyl acetate, poured into a separatoryfunnel and extracted with NaHCO₃ aqueous saturated solution. The organicphase was dried over Na₂SO₄ and evaporated down to dryness. The crudematerial was purified by flash chromatography (SiO₂, 20 g, gradientethyl acetate in heptane) gave 92 mg of the title compound as whitepowder (Yield 73%). MS (ESI, m/z): 336.4 (MH+).

Example 713-[5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-cyclopropyl-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 70d, using5-chloro-N-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide andcyclopropanecarboxylic acid (CAS 1759-53-1) as starting materials, withHATU (Eq: 1.2) and DIPEA (Eq: 2.0), and heated with microwave 30 min at120° C. MS (ESI, m/z): 320.4 (MH+).

Example 725-cyclopropyl-3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 33b, using5-cyclopropyl-N′-hydroxy-4-(2,2,2-trifluoroethoxy)picolinimidamide andcyclopropanecarbonyl chloride (CAS 4023-34-1) as starting materials, andpurified by purified by flash chromatography. MS (ESI, m/z): 326.6(MH+).

Example 731-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]pyrrolidin-3-ol

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3-pyrrolidinol (CAS 40499-83-0) (Eq: 2.0) as starting materials in NMPwith K₂CO₃ (Eq: 3.0), heated 1 h30 at 200° C. with microwave, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 329.6(MH+).

Example 745-tert-butyl-3-[5-cyclopropyl-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3,3,4,4-tetrafluoropyrrolidine hydrochloride (CAS 1810-13-5) (Eq: 2.0)as starting materials in Sulfolane with K₂CO₃ (Eq: 3.0), heated 2 h at180° C. with microwave, and purified by preparative HPLC without anywork-up. MS (ESI, m/z): 385.6 (MH+).

Example 755-tert-butyl-3-[5-cyclopropyl-4-(4-methylsulfonylphenoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and4-methylsulfonylphenol (CAS 14763-60-1) (Eq: 1.2) as starting materialsin NMP, heated 1 h at 180° C. with microwave, and purified bypreparative HPLC without any work-up. MS (ESI, m/z): 414.6 (MH+).

Example 767-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]-2-oxa-7-azaspiro[3.4]octane

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and2-oxa-6-azaspiro[3.4]octane (CAS 220290-68-6) (Eq: 2.0) as startingmaterials in NMP with K₂CO₃ (Eq: 3.0), heated 1 h30 at 200° C. withmicrowave, and purified by preparative HPLC without any work-up. MS(ESI, m/z): 355.6 (MH+).

Example 775-tert-butyl-3-[5-cyclopropyl-4-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3,3-difluoropyrrolidine hydrochloride (CAS 163457-23-6) (Eq: 2.0) asstarting materials in Sulfolane with K₂CO₃ (Eq: 3.0), heated 30 min at220° C. with microwave, and purified by preparative HPLC without anywork-up. MS (ESI, m/z): 349.6 (MH+).

Example 784-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]morpholine

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andmorpholine (CAS 110-91-8) (Eq: 1.2) as starting materials in DMSO withCsF (Eq: 1) and triethylamine (Eq: 2.0), heated 24 h at 150° C., andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 329.6(MH+).

Example 795-tert-butyl-3-(5-cyclopropyl-4-pyrrolidin-1-ylpyridin-2-yl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andpyrrolidine (CAS 123-75-1) (Eq: 2) as starting materials in NMP withK₂CO₃ (Eq: 3.0), heated 1 h30 at 200° C. with microwave, and purified bypreparative HPLC without any work-up. MS (ESI, m/z): 313.3 (MH+).

Example 805-tert-butyl-3-(5-cyclopropyl-4-cyclopropylsulfonylpyridin-2-yl)-1,2,4-oxadiazole

To a solution of5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole (50mg, 0.18 mmol), previously described as Example 48d, in DMA (2 mL) in amicrowave vial, was added sodium cyclopropanesulfinate (CAS 910209-21-1)(46.1 mg, 0.36 mmol, Eq: 2.0) and DMAP (44 mg, 0.36 mmol, Eq: 2.0). Tubewas sealed and reaction heated 2 days at 140° C. DMA was evaporated.Crude was then extracted with ethyl acetate/NaHCO₃ aqueous saturatedsolution. Organic layer was dried on Na₂SO₄ and evaporated. Column onSiO₂ with a gradient ethyl acetate/heptane gave 37 mg of the titlecompound as colorless viscous oil (Yield 59%). MS (ESI, m/z): 348.6(MH+).

Example 815-tert-butyl-3-[5-cyclopropyl-4-(3-methoxyazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3-methoxyazetidine (CAS 110925-17-2) (Eq: 2.0) as starting materials inethylene glycol with Cs₂CO₃ (Eq: 3.0), heated 6 h at 100° C., andpurified by preparative HPLC after filtration. MS (ESI, m/z): 329.6(MH+).

Example 826-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]-2-oxa-6-azaspiro[3.3]heptane

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and2-oxa-6-azaspiro[3.3]heptane (CAS 174-78-7) (Eq: 2) as startingmaterials in ethylene glycol with Cs₂CO₃ (Eq: 3), heated 6 h at 100° C.,and purified by preparative HPLC after filtration. MS (ESI, m/z): 341.6(MH+).

Example 835-tert-butyl-3-[5-cyclopropyl-4-(2-ethoxyethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and2-ethoxyethanol (CAS 110-80-5) as starting materials, and purified bypreparative HPLC without any work-up. MS (ESI, m/z): 332.6 (MH+).

Example 845-tert-butyl-3-[5-cyclopropyl-4-(1-methoxybutan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-methoxybutan-2-ol (CAS 53778-73-7) as starting materials, and purifiedby preparative HPLC without any work-up. MS (ESI, m/z): 346.6 (MH+).

Example 855-tert-butyl-3-[5-cyclopropyl-4-[2-[(2-methylpropan-2-yl)oxy]ethoxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andethylene glycol mono-tert-butyl ether (CAS 7580-85-0) as startingmaterials, and purified by preparative HPLC without any work-up. MS(ESI, m/z): 360.7 (MH+).

Example 865-tert-butyl-3-[5-cyclopropyl-4-[1-[(2-methylpropan-2-yl)oxy]propan-2-yloxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-tert-butoxy-propan-2-ol (CAS 57018-52-7) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 374.8(MH+).

Example 875-tert-butyl-3-[5-cyclopropyl-4-(1-methoxypropan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-methoxy-propan-2-ol (CAS 107-98-2) as starting materials, and purifiedby preparative HPLC without any work-up. MS (ESI, m/z): 332.7 (MH+).

Example 885-tert-butyl-3-[5-cyclopropyl-4-(oxan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andtetrahydro-pyran-3-ol (CAS 19752-84-2) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 344.6(MH+).

Example 895-tert-butyl-3-[5-cyclopropyl-4-(3-methoxybutoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3-methoxy-butanol (CAS 2517-43-3) as starting materials, and purified bypreparative HPLC without any work-up. MS (ESI, m/z): 346.6 (MH+).

Example 905-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3-oxetanemethanol (CAS 6246-06-6) as starting materials, and purified bypreparative HPLC without any work-up. MS (ESI, m/z): 330.6 (MH+).

Example 915-cyclopropyl-3-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 33b, using(S,Z)-5-cyclopropyl-N′-hydroxy-4-(1,1,1-trifluoropropan-2-yloxy)picolinimidamide(prepared in analogy to Example 33a but with(S)-1,1,1-trifluoropropan-2-ol for the first Example 7a) and isobutyrylchloride (CAS 79-30-1) as starting materials, and purified by purifiedby flash chromatography. MS (ESI, m/z): 340.1 (MH+).

Example 925-tert-butyl-3-[5-cyclopropyl-4-(1-ethylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-ethyl-3-pyrrolidinol (CAS 30727-14-1) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 357.6(MH+).

Example 935-tert-butyl-3-[5-cyclopropyl-4-(1-propan-2-ylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-isopropyl-pyrrolidinol (CAS 42729-56-6) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 371.7(MH+).

Example 945-tert-butyl-3-[5-cyclopropyl-4-(2-pyrrolidin-1-ylethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-(2-hydroxyethyl)pyrrolidine (CAS 2955-88-6) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 357.6(MH+).

Example 955-tert-butyl-3-[5-cyclopropyl-4-(2-piperidin-1-ylethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-(2-hydroxyethyl)piperidine (CAS 3040-44-6) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 371.7(MH+).

Example 965-tert-butyl-3-[5-cyclopropyl-4-(1-piperidin-1-ylpropan-2-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andalpha-methyl-1-piperidineethanol (CAS 934-90-7) as starting materials,and purified by preparative HPLC without any work-up. MS (ESI, m/z):385.7 (MH+).

Example 975-tert-butyl-3-[5-cyclopropyl-4-[(1-methylpiperidin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-methyl-2-piperidinemethanol (CAS 20845-34-5) as starting materials,and purified by preparative HPLC without any work-up. MS (ESI, m/z):371.7 (MH+).

Example 982-tert-butyl-5-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,3,4-oxadiazolea) 5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinonitrile

To a solution of 4-chloro-5-cyclopropylpicolinonitrile (300 mg, 1.68mmol, Eq: 1.00), previously described as Example 48b, in dry DMF (11 mL)with tetrahydro-2H-pyran-4-ol (CAS 2081-44-9) (189 mg, 176 μL, 1.85mmol, Eq: 1.1) was added NaH (60% in oil, 73.9 mg, 1.85 mmol, Eq: 1.1).The reaction was stirred at RT 15 min then 30 min at 110° C. withmicrowave. The solvent was partially evaporated. Extraction with ethylacetate/NaHCO₃ saturated aqueous solution Organic layer dried on Na₂SO₄and evaporated. Column on SiO₂ using MPLC ISCO with a gradientheptane/ethyl acetate gave 245 mg of the title compound as off-whitepowder (Yield 59%). MS (ESI, m/z): 245.6 (MH+).

b) 5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinic Acid

5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinonitrile (240 mg,0.982 mmol, Eq: 1.00) was dissolved in HCl 25% aqueous solution (9 mL).Reaction was heated at 110° C. After 3 h reaction was complete andcooled down to RT. HCl was neutralized using 6M NaOH aqueous solutionfollowed by NaOH pellets. Then pH adjusted to 1-2 with HCl 2M. Theprecipitate formed was filtered off to give 140 mg of the title compoundas light yellow powder (Yield 54%). MS (ESI, m/z): 264.6 (MH+).

c)5-cyclopropyl-N′-pivaloyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinohydrazide

5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinic acid (70 mg, 266μmol, Eq: 1.00) in 1,2-Dichloroethane (1.33 mL) had thionyl chloride(47.4 mg, 29.1 μL, 399 μmol, Eq: 1.5) added to it. The reaction mixturewas heated up to 90° C. and left to reflux for 3 h. The reaction wascomplete and the reaction mixture was concentrated in vacuo. The productwas used immediately in the next step and dissolved in THF (391 μL) tobe reacted with pivalohydrazide (35.0 mg, 292 μmol, Eq: 1.1) andtriethylamine (40.4 mg, 55.6 μL, 399 μmol, Eq: 1.5) at RT overnight. Thereaction mixture was then diluted with ethyl acetate, poured into NaHCO₃aqueous solution (1M). It was then extracted with ethyl acetate and theorganic layers were combined, dried, and concentrated in vacuo to beused as a crude. MS (ESI, m/z): 362.6 (MH+).

d)2-tert-butyl-5-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,3,4-oxadiazole

Trifluoromethanesulfonic anhydride (97.7 mg, 58.5 μL, 346 μmol, Eq: 1.5)was added slowly to a solution of triphenylphosphine oxide (193 mg, 692μmol, Eq: 3.0) in dry DCM (0.231 mL) at 0° C. The reaction mixture wasstirred for 5 minutes at this temperature before it was adjusted to roomtemperature and5-cyclopropyl-N′-pivaloyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinohydrazide(83.4 mg, 231 μmol, Eq: 1.00), first azeotropically dried with toluene,was added. The reaction mixture was then stirred for a further 30minutes at RT before monitoring via LC-MS showed the reaction ascomplete. The reaction mixture was then diluted with DCM and poured intoNaHCO₃ saturated aqueous solution and extracted with DCM. The aqueouslayer was then back-extracted with DCM before the organic layers werecombined, dried, and concentrated in vacuo. The crude material waspurified by flash chromatography (SiO₂, 10 g, gradient ethyl acetate inheptane) to give 33.9 mg of the title compound (Yield 42%). MS (ESI,m/z): 344.6 (MH+).

Example 995-tert-butyl-3-[5-cyclopropyl-4-(1-methylpiperidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3-hydroxy-N-methylpiperidine (CAS 3554-74-3) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 357.7(MH+).

Example 1005-tert-butyl-3-[5-cyclopropyl-4-(1-ethylpiperidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3-hydroxy-N-ethylpiperidine (CAS 13444-24-1) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 371.7(MH+).

Example 1012-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxy-N,N-diethylpropan-1-amine

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and1-diethylamino-2-propanol (CAS 4402-32-8) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 373.7(MH+).

Example 1023-[[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxymethyl]morpholine

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3-hydroxymethylmorpholine (CAS 103003-01-6) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 359.6(MH+).

Example 1034-[2-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxyethyl]morpholine

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole andN-(2-hydroxyethyl)morpholine (CAS 622-40-2) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 373.7(MH+).

Example 1045-tert-butyl-3-(5-cyclopropyl-4-piperidin-3-yloxypyridin-2-yl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(R,S)-Boc-3-hydroxypiperidine (CAS 85275-45-2) as starting materials.The reaction was then diluted with ethyl acetate and washed with water.Organic layer was dried on Na₂SO₄ and evaporated. Product was used as acrude and directly dissolved in HCl (4M) in dioxane and stirred at RTfor 2 h. The reaction mixture was purified by preparative HPLC afterevaporation of the solvent. MS (ESI, m/z): 343.7 (MH+).

Example 1055-tert-butyl-3-[5-cyclopropyl-4-[(3-fluorooxetan-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(3-fluoro-oxetane) methanol (CAS 865451-85-0) as starting materials, andpurified by preparative HPLC without any work-up. MS (ESI, m/z): 348.5(MH+).

Example 1065-tert-butyl-3-[5-cyclopropyl-4-[(2,5-dimethyl-1,3-oxazol-4-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(2,5-dimethyloxazol-4-yl)methanol (CAS 92901-94-5) as startingmaterials, and purified by preparative HPLC without any work-up. MS(ESI, m/z): 369.6 (MH+).

Example 1075-tert-butyl-3-[5-cyclopropyl-4-[(5-methyl-1,2-oxazol-3-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and(5-methylisoxazol-3-yl)methanol (CAS 35166-33-7) as starting materials,and purified by preparative HPLC without any work-up. MS (ESI, m/z):355.6 (MH+).

Example 1085-tert-butyl-3-[5-cyclopropyl-4-(3-methylsulfonylphenoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3-(methylsulfonyl)phenol (CAS 14763-61-2) as starting materials withCs₂CO₃ (Eq: 1.5), and purified by preparative HPLC without any work-up.MS (ESI, m/z): 414.5 (MH+).

Example 1095-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazolea) 3-(4,6-dichloropyridin-3-yl)oxetan-3-ol

To a solution of 5-bromo-2,4-dichloropyridine (15 g, 66.1 mmol, Eq:1.00) (CAS 849937-96-8) in dry THF (300 mL) cooled down to −15° C. underan argon atmosphere was added isopropyl magnesium chloride, lithiumchloride complex (53.4 mL, 69.4 mmol, Eq: 1.05) and the mixture wasstirred at −15° C. for 1 h. Slow addition of neat oxetan-3-one (5.24 g,72.7 mmol, Eq: 1.1) to the reaction mixture cooled at −15° C. andreaction mixture was let to warm up to RT overnight. Reaction wasmonitored by LC-MS. Reaction was quenched by addition of water and wastransferred into a separatory funnel. Dilution with ethyl acetate,extraction with saturated aqueous NH₄Cl and organic phase was collected.Aqueous phase was back-extracted with ethyl acetate; organic phases werecombined, dried over Na₂SO₄ and evaporated down to dryness. Flashchromatography with a 330 g SiO₂ column, eluent mixture of heptane andethyl acetate gave 10.5 g of the desired product as a white solid (yield72%). MS (ESI, m/z): 220.4 (MH+).

b) 4-chloro-5-(3-hydroxyoxetan-3-yl)picolinonitrile

To a solution of 3-(4,6-dichloropyridin-3-yl)oxetan-3-ol (5.0 g, 22.7mmol, Eq: 1.00) in dry DMF (100 mL) under argon atmosphere was addeddicyanozinc (1.47 g, 12.5 mmol, Eq: 0.55), dppf (1.26 g, 2.27 mmol, Eq:0.1) and Pd₂(dba)₃ (1.04 g, 1.14 mmol, Eq: 0.05). The reaction mixturewas stirred at 100° C. for 2 h and monitored by LC-MS. Evaporation ofDMF, residue was diluted with ethyl acetate and poured into a separatoryfunnel. Extraction with saturated aqueous NH₄Cl. Pd colloids were formedand removed by filtration through Celite. Organic phase was collected;aqueous phase was back-extracted with ethyl acetate. Organic phases werecombined, dried over Na₂SO₄ and evaporated down to dryness. Flashchromatography with a 120 g SiO₂ column, eluent mixture of heptane andethyl acetate gave 4.1 g of the desired product (Yield 86%). MS (ESI,m/z): 209.0 (MH−).

c) 4-chloro-5-(3-fluorooxetan-3-yl)pyridine-2-carbonitrile

To a solution of 4-chloro-5-(3-hydroxyoxetan-3-yl)picolinonitrile (0.2g, 950 μmol, Eq: 1.00) in dry DCM (6 mL) cooled down to −78° C. wasadded DAST (161 mg, 132 μL, 997 μmol, Eq: 1.05). The reaction wasstirred at −78° C. for 15 min, let to warm up to 0° C. and stirred at 0°C. for 1 h. Reaction was then quenched by addition of aqueous Na₂CO₃ 2M,the mixture was stirred at RT for 15 min and poured into a separatoryfunnel. Extraction, organic phase was collected, dried over Na₂SO₄ andevaporated down to dryness. Flash chromatography with a 20 g SiO₂column, eluent mixture of heptane and ethyl acetate gave 184 mg of thedesired product (Yield 91%). MS (ESI, m/z): 213.0 (MH+).

d) 4-chloro-5-(3-fluorooxetan-3-yl)-N′-hydroxypyridine-2-carboximidamide

To a solution of 4-chloro-5-(3-fluorooxetan-3-yl)picolinonitrile (500mg, 2.35 mmol, Eq: 1.00) in Ethanol (15 mL) was added hydroxylaminehydrochloride (196 mg, 2.82 mmol, Eq: 1.2) and triethylamine (476 mg,656 μL, 4.7 mmol, Eq: 2.0). The reaction mixture was heated to 50° C.and stirred for 3 hours. Evaporation of volatiles, residue redissolvedin ethyl acetate, poured into a separatory funnel and extracted withaqueous NaHCO₃ 1M, The organic layers were dried over Na₂SO₄ andevaporated down to dryness. Flash chromatography with a 20 g SiO₂column, eluent mixture of heptane and ethyl acetate gave 490 mg ofdesired compound (Yield 84%). MS (ESI, m/z): 246.4 (MH+).

e)5-tert-butyl-3-[4-chloro-5-(3-fluorooxetan-3-yl)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of4-chloro-5-(3-fluorooxetan-3-yl)-N′-hydroxypicolinimidamide (490 mg,1.99 mmol, Eq: 1.00) in dry DMF (7 mL) under argon atmosphere was addedK₂CO₃ (358 mg, 2.59 mmol, Eq: 1.3) and slowly pivaloyl chloride (CAS3282-30-2) (265 mg, 270 μL, 2.19 mmol, Eq: 1.1). The reaction mixturewas stirred for 1 h at RT and controlled by LC-MS. The reaction was thenstirred at 130° C. for 1 h30 and monitored by LC-MS. The reactionmixture was poured into a separatory funnel, diluted with EtOAc andextracted with aqueous NaHCO₃ 1M. The organic layer was dried overNa₂SO₄ and evaporated down to dryness. Purification by flashchromatography gave 374 mg of the title compound (Yield 54%). MS (ESI,m/z): 312.5 (MH+).

f)5-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of5-tert-butyl-3-(4-chloro-5-(3-fluorooxetan-3-yl)pyridin-2-yl)-1,2,4-oxadiazole(50 mg, 144 μmol, Eq: 1.00) in dry DMF (1 mL) were added NaH (6.35 mg,159 μmol, Eq: 1.1) and tetrahydropyran-4-ol (16.2 mg, 159 μmol, Eq: 1.1)(CAS 2081-44-9). The reaction was stirred at RT for 15 min and thenstirred at 110° C. for 30 min under microwave radiation, reaction wasmonitored by LC-MS. Reaction was quenched by addition of few drops ofwater, and mixture was directly purified by preparative HPLC with anywork-up procedure giving 43 mg of the title compound. MS (ESI, m/z):378.6 (MH+).

Example 1105-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 109f, using5-tert-butyl-3-(4-chloro-5-(3-fluorooxetan-3-yl)pyridin-2-yl)-1,2,4-oxadiazoleand 4-fluorophenol (CAS 371-41-5) as starting materials, and purified bypreparative HPLC without any work-up. MS (ESI, m/z): 388.5 (MH+).

Example 1113-[2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-5H-1,3-oxazol-4-yl]-5-methyl-1,2,4-oxadiazolea) N-(1-(benzyloxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide

To a solution of 1-(benzyloxy)propan-2-one (4.0 g, 21.9 mmol, Eq: 1.00)(CAS 22539-93-1) in dry THF (100 mL) under argon atmosphere was added2-methylpropane-2-sulfinamide (2.79 g, 23.0 mmol, Eq: 1.05) (CAS146374-27-8) and Titanium(IV) ethoxide (5.25 g, 4.83 mL, 23.0 mmol, Eq:1.05). The reaction mixture was stirred at 70° C. overnight. Reactionwas cooled down to RT and stirred during quenching by addition of 10 mLof aqueous saturated NaCl solution. The heterogenous mixture was stirredfor 20 min, then filtered through a pad of Celite and finally thefiltrate was concentrated, diluted with ethyl acetate and extracted withaqueous saturated NaCl solution. Organic phase collected, dried overNa₂SO₄ and evaporated down to dryness. Flash chromatography with a 120 gSiO₂ column, eluent mixture of heptane and ethyl acetate, gave 2.62 g ofthe title compound as yellow oil (Yield 45%). MS (ESI, m/z): 268.6(MH+).

b) N-(1-(benzyloxy)-2-cyanopropan-2-yl)-2-methylpropane-2-sulfinamide

To a solution ofN-(1-(benzyloxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide (2.6 g,9.72 mmol, Eq: 1.00) in dry THF (45 mL) under argon atmosphere was addedCsF (1.62 g, 10.7 mmol, Eq: 1.1) followed by trimethylsilyl cyanide(1.06 g, 1.43 mL, 10.7 mmol, Eq: 1.1). The reaction mixture was stirredat RT overnight and monitored by TLC (ethyl acetate, spray reagentKMnO₄). Concentration in vacuo, dilution with ethyl acetate, extractionwith water, organic phase was brined before drying over Na₂SO₄ andevaporated down to dryness. Flash chromatography with a 70 g SiO₂column, eluent mixture of heptane and ethyl acetate, gave 2.55 g of thedesired product (Yield 89%). MS (ESI, m/z): 295.5 (MH+).

c)3-(benzyloxy)-2-(1,1-dimethylethylsulfinamido)-N′-hydroxy-2-methylpropanimidamide

To a suspension of potassium carbonate (2.44 g, 17.6 mmol, Eq: 1.5) indry ethanol (40 mL) under argon atmosphere was added hydroxylaminehydrochloride (858 mg, 12.3 mmol, Eq: 1.05) and the mixture was stirredat RT for 20 min. Addition of a solution ofN-(1-(benzyloxy)-2-cyanopropan-2-yl)-2-methylpropane-2-sulfinamide (3.46g, 11.8 mmol, Eq: 1.00) in dry ethanol (30 mL) to the former reactionmixture. The reaction mixture was stirred at 55° C. overnight andmonitored by TLC (ethyl acetate, UV 254 nm and spray reagent KMnO₄).Evaporation of volatiles, residue suspended in ethyl acetate, extractionwith aqueous Na₂CO₃ 2M, aqueous phase back-extracted with ethyl acetate,organic phase were combined, dried over Na₂SO₄ and evaporated down todryness. Flash chromatography with a 50 g SiO₂ column, eluent mixture ofDCM and methanol, gave 3.1 g of the title compound as a white solid(Yield 81%). MS (ESI, m/z): 328.6 (MH+).

d)N-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-2-methylpropane-2-sulfinamide

To a solution of3-(benzyloxy)-2-(1,1-dimethylethylsulfinamido)-N′-hydroxy-2-methylpropanimidamide(3.1 g, 9.47 mmol, Eq: 1.00) in dry DMF (50 mL) under argon atmospherewas added potassium carbonate (1.57 g, 11.4 mmol, Eq: 1.2) and aceticanhydride (967 mg, 893 μL, 9.47 mmol, Eq: 1.0). The reaction mixture wasstirred at RT for 1 h and was monitored by LC-MS to control theformation of the acetylated intermediate. The reaction was then stirredat 120° C. for 2 h, monitoring was done by LC-MS. Evaporation ofvolatiles, residue redissolved in ethyl acetate, extraction with aqueousNaHCO₃ 1M, aqueous phase back-extracted with ethyl acetate, organicphases were combined, dried over Na₂SO₄ and evaporated down to dryness.Flash chromatography with a 120 g SiO₂ column, eluent mixture of heptaneand ethyl acetate, gave 2.25 g of title compound as yellow oil (Yield68%). MS (ESI, m/z): 352.6 (MH+).

e) 1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine

To a solution ofN-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-2-methylpropane-2-sulfinamide(2.25 g, 6.4 mmol, Eq: 1.00) in MeOH (25 mL) was added HCl 4M in Dioxane(4.8 mL, 19.2 mmol, Eq: 3.0). The reaction mixture was stirred at RT for1 h and monitored by LC-MS. Evaporation of volatiles, residueredissolved in ethyl acetate, extraction with aqueous Na₂CO₃ 2M. Aqueousphase was back-extracted with ethyl acetate and organic phases werecombined, dried over Na₂SO₄ and evaporated down to dryness. Flashchromatography with a 50 g SiO₂ column, eluent mixture of heptane andethyl acetate, gave 1.52 g of desired product as light yellow oil (Yield96%). MS (ESI, m/z): 248.6 (MH+).

f)N-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamide

To a solution of 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid(0.4 g, 1.53 mmol, Eq: 1.00), previously described as Example 7e, in dryDMF (10 mL) under argon atmosphere was added TBTU (516 mg, 1.61 mmol,Eq: 1.05) and triethylamine (186 mg, 256 μL, 1.84 mmol, Eq: 1.2). Thereaction mixture was stirred at RT for 30 min and1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine (398 mg,1.61 mmol, Eq: 1.05) was then added to the reaction. The reaction wasthen stirred at RT overnight and monitored by LC-MS. Evaporation of DMF.Residue was redissolved in ethyl acetate and extracted with aqueousNaHCO₃ 1M. Organic phase dried over Na₂SO₄ and evaporated down todryness. Flash chromatography with a 50 g SiO₂ column, eluent mixture ofheptane and ethyl acetate gave 805 mg of the desired product (Yield93%). MS (ESI, m/z): 491.5 (MH+).

g)5-cyclopropyl-N-(1-hydroxy-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-4-(2,2,2-trifluoroethoxy)picolinamide

To a solution ofN-(1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamide(0.1 g, 204 mol, Eq: 1.00) in dry DCM (1 mL) cooled down to 0° C. underargon atmosphere was added BBr₃ solution 1.0M in DCM (224 μL, 224 μmol,Eq: 1.1). The reaction mixture was stirred at 0° C. for 15 min and thenstirred at RT for 1 h, reaction was monitored by LC-MS. Reaction wasdiluted with DCM, quenched by addition of aqueous Na₂CO₃ 2M and mixturewas stirred for 10 min. Mixture was poured into a separatory funnel,organic phase was collected, aqueous phase was back-extracted with DCM,organic phases were combined, dried over Na₂SO₄ and evaporated down todryness. Flash chromatography with a 10 g SiO₂ column, eluent mixture ofheptane and ethyl acetate, gave 80 mg of the desired product (Yield92%). MS (ESI, m/z): 401.5 (MH+).

h)2-(5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamido)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propyl4-methylbenzenesulfonate

To a solution of5-cyclopropyl-N-(1-hydroxy-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-4-(2,2,2-trifluoroethoxy)picolinamide(0.1 g, 250 mol, Eq: 1.00) in dry DCM (2 ml) was added DMAP (15.3 mg,125 mol, Eq: 0.5), K₂CO₃ (48.3 mg, 350 mol, Eq: 1.4) followed byaddition of 4-methylbenzene-1-sulfonyl chloride (47.6 mg, 250 μmol, Eq:1.0). The reaction mixture was stirred at RT overnight and monitored byLC-MS. Reaction diluted with DCM and water, poured into a separatoryfunnel, extracted and organic phase was collected. Organic phase wasdried over Na₂SO₄ and evaporated down to dryness. Crude was used for thenext step without any purification. MS (ESI, m/z): 555.4 (MH+).

i)3-(2-(5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-4-methyl-4,5-dihydrooxazol-4-yl)-5-methyl-1,2,4-oxadiazole

To a solution of2-(5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamido)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propyl4-methylbenzenesulfonate (0.06 g, 108 μmol, Eq: 1.00) in dry DMF (1 mL)was added triethylamine (16.4 mg, 22.6 μl, 162 μmol, Eq: 1.5) and3,3-difluoroazetidine hydrochloride (CAS 288315-03-7) (16.8 mg, 130μmol, Eq: 1.2). The reaction mixture was stirred at 80° C. for 45 minunder microwave radiation and reaction was monitored by LC-MS whichshowed conversion to a side product from an intramolecular ring closureto an oxazolidine. Reaction was directly purified by preparative HPLCwithout any purification and gave 6.2 mg of the title compound. MS (ESI,m/z): 383.5 (MH+).

Example 1125-tert-butyl-3-(6-chloro-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridin-2-yl)-1,2,4-oxadiazolea)2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridine1-oxide

To a solution of5-tert-butyl-3-(5-cyclopropyl-4-(4-fluorobenzyloxy)pyridin-2-yl)-1,2,4-oxadiazole(326 mg, 887 μmol, Eq: 1.00), previously described as Example 53, in dryDCM (4.93 mL) was added m-CPBA (459 mg, 1.33 mmol, Eq: 1.5) and thereaction stirred overnight at RT. Extraction with NaHCO₃/DCM. Organiclayer was dried on Na₂SO₄ and evaporated. Purification by flashchromatography on SiO₂ column with a gradient DCM and methanol gave 445mg of the title compound (Yield 78%). MS (ESI, m/z): 384.6 (MH+).

b)5-tert-butyl-3-(6-chloro-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridin-2-yl)-1,2,4-oxadiazole

2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropyl-4-(4-fluorobenzyloxy)pyridine1-oxide (123 mg, 321 μmol, Eq: 1.00) was dissolved in a mixture ofDCM/DMF: 1/1 (2.8 mL). The mixture was cooled down to 0° C. and oxalylchloride (204 mg, 139 μL, 1.6 mmol, Eq: 5.0) was slowly added. Reactionwas stirred at 0° C. for 30 min and then the temperature was allowed toreach RT and reacted overnight. The reaction was cooled down to 0° C.and quenched by addition of aqueous Na₂CO₃ and stirred for 15 min at 0°C. The mixture was diluted with ethyl acetate and extracted with aqueousNa₂CO₃. Organic phase was collected; aqueous phase was back-extractedwith ethyl acetate. Organic phases were combined, dried over Na₂SO₄ andevaporated down to dryness. The crude material was purified by flashchromatography on SiO₂ using MPLC ISCO with a gradient heptane/ethylacetate giving 15 mg of the title compound as colorless viscous oil. MS(ESI, m/z): 402.5 (MH+).

Example 1132-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,3,4-oxadiazolea) 5-cyclopropyl-N′-pivaloyl-4-(2,2,2-trifluoroethoxy)picolinohydrazide

5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (100 mg, 383 mmol,Eq: 1.00), previously described as Example 7e, in DCM (1.91 mL) hadoxalyl chloride (50 μL, 0.574 mmol, Eq: 1.5) and DMF (2 μL, 0.019 mmol,Eq: 0.05) added to it. The reaction was deemed to be complete and thereaction mixture was concentrated in vacuo. The product was usedimmediately in the next step and dissolved in THF (563 μL) to be reactedwith pivalohydrazide (55.0 mg, 459 μmol, Eq: 1.2) (CAS 42826-42-6) andtriethylamine (58.1 mg, 80.0 μL, 574 μmol, Eq: 1.5) at RT overnight. Thereaction mixture was then diluted with ethyl acetate, poured into NaHCO₃1M solution. It was then extracted with ethyl acetate and the organiclayers were combined, dried, and concentrated in vacuo to give 130 mg ofthe title compound used as crude (Yield 94%). MS (ESI, m/z): 360.6(MH+).

b)2-tert-butyl-5-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,3,4-oxadiazole

Trifluoromethanesulfonic anhydride (153 mg, 91.7 μL, 543 μmol, Eq: 1.5)was added slowly to a solution of triphenylphosphine oxide (302 mg, 1.09mmol, Eq: 3.0) in dry DCM (0.231 mL) at 0° C. The reaction mixture wasstirred for 5 minutes at this temperature before it was adjusted to roomtemperature and5-cyclopropyl-N′-pivaloyl-4-(2,2,2-trifluoroethoxy)picolinohydrazide(130 mg, 362 μmol, eq: 1.00) previously azeotropically dried withtoluene, was added. The reaction mixture was then stirred for a further30 minutes at RT before monitoring via LC-MS showed the reaction ascomplete. The reaction mixture was then diluted with DCM and poured intoNaHCO₃ saturated aqueous solution and extracted with DCM. The aqueouslayer was then back-extracted with DCM before the organic layers werecombined, dried, and concentrated in vacuo. The crude material waspurified by flash chromatography (SiO₂, 10 g, gradient ethyl acetate inheptane) to give 56 mg of the title product as white solid (45% yield).MS (ESI, m/z): 342.6 (MH+).

Example 1145-tert-butyl-3-[6-chloro-5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazolea)2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridine1-oxide

To a solution of5-tert-butyl-3-(5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)-1,2,4-oxadiazole(64 mg, 186 μmol, Eq: 1.00), previously described as Example 63, in dryDCM (1.04 mL) was added m-CPBA (96.5 mg, 280 μmol, Eq: 1.5). Thereaction was stirred for 1 h at RT. Extraction NaHCO₃/DCM. Organic layerwas dried on Na₂SO₄ and evaporated. Purification by flash chromatography(SiO₂, 70 g, eluent: ethyl acetate/heptane) gave 59 mg of the desiredcompound (Yield 88%). MS (ESI, m/z): 360.6 (MH+).

b)5-tert-butyl-3-[6-chloro-5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole

2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridine1-oxide (56 mg, 0.156 mmol, Eq: 1.00) was dissolved in a mixture ofDCM/DMF: 1/1 (1.3 mL). The mixture was cooled down to 0° C. and oxalylchloride (98.9 mg, 67.3 μL, 779 μmol, Eq: 5.0) was slowly added.Reaction was stirred at 0° C. for 20 min and then the temperature wasallowed to reach RT and reacted overnight. Another 1.5 eq of oxalylchloride was added and stirred for 1.5 h. The reaction was then cooleddown to 0° C. and quenched by addition of aqueous Na₂CO₃ and stirred for15 min at 0° C. The mixture was diluted with ethyl acetate and extractedwith aqueous Na₂CO₃. Organic phase was collected; aqueous phase wasback-extracted with ethyl acetate. Organic phases were combined, driedover Na₂SO₄ and evaporated down to dryness. The crude material waspurified by flash chromatography (SiO₂, 5 g, ethyl acetate/heptane)giving 21 mg of the title compound as colorless oil (Yield 35%). MS(ESI, m/z): 378.5 (MH+).

Example 1155-tert-butyl-3-[5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazolea) 5-cyclopropyl-4-(2,2-difluoroethoxy)picolinonitrile

Sodium hydride (123 mg, 3.08 mmol, Eq: 1.1) was added to a solution of4-chloro-5-cyclopropylpicolinonitrile (500 mg, 2.8 mmol, Eq: 1.00),previously described as Example 48b, and 2,2-difluoroethanol (253 mg,3.08 mmol, Eq: 1.1) (CAS 359-13-7) in DMF (10 mL) at RT. and stirred for3 hours. The 5-fold volume of water was added, followed by extractionwith EtOAc, washing with brine. Organic layer was dried on MgSO₄,concentrated in vacuo and chromatographed on SiO₂ with DCM to afford 508mg of the title compound as a dark-yellow solid (Yield 80%). MS (ESI,m/z): 225.2 (MH+).

b)5-tert-butyl-3-[5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

To a solution of 5-cyclopropyl-4-(2,2-difluoroethoxy)picolinonitrile(120 mg, 0.535 mmol, Eq: 1.00) in EtOH (3.5 mL) was added triethylamine(149 μL, 1.07 mmol, Eq: 2.0) and hydroxylamine hydrochloride (55.8 mg,0.803 mmol, Eq: 1.5) and the mixture heated 30 min at 90° C. withmicrowave. 1 M NaHCO₃ was added and it was extracted with DCM. Drying onMgSO₄ and concentration in vacuo afforded 60 mg of the compound aslight-yellow solid, this was used without further purification anddissolved in DMF (2.00 mL). Then triethylamine (29.0 mg, 40.0 μL, 287μmol, Eq: 1.2) and pivaloyl chloride (31.4 mg, 32 μL, 260 μmol, Eq: 1.1)were added at RT and after 30 minutes stirring, the solution was heatedat 130° C. with microwave for 30 minutes. The mixture was diluted withwater and extracted with ethyl acetate, washed with brine, dried onMgSO₄ and concentration in vacuo followed by column chromatography(SiO₂, ethyl acetate in heptane) afforded 45 mg of the title compound(Yield 59%). MS (ESI, m/z): 324.5 (MH+).

Example 1165-tert-butyl-3-[5-cyclopropyl-4-(2-fluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 115, using4-chloro-5-cyclopropylpicolinonitrile, previously described as Example48b, and 2-fluoroethanol (CAS 371-62-0) as starting materials. MS (ESI,m/z): 306.5 (MH+).

Example 1175-tert-butyl-3-[5-cyclopropyl-4-(pyridin-2-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and2-(hydroxymethyl)pyridine (CAS 586-98-1) as starting materials, heated30 min at 120° C. with microwave and purified by preparative HPLCwithout any work-up. MS (ESI, m/z): 351.6 (MH+).

Example 1185-tert-butyl-3-[5-cyclopropyl-4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and5-fluoro-2-hydroxylmethylpyridine (CAS 802325-29-7) as startingmaterials, heated 30 min at 110° C. under microwave radiation. Themixture was diluted with ethyl acetate and extracted with aqueousNa₂CO₃. Organic phase was collected and the aqueous phase wasback-extracted with ethyl acetate. The organic phases were combined,dried over Na₂SO₄ and evaporated down to dryness. The crude material waspurified by flash chromatography (SiO₂, 5 g, ethyl acetate/heptane). MS(ESI, m/z): 369.6 (MH+).

Example 1195-tert-butyl-3-[5-cyclopropyl-4-(pyridin-3-ylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 48e, using5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole and3-(hydroxymethyl)pyridine (CAS 100-55-0) as starting materials, heated30 min at 110° C. under microwave radiation. The mixture was dilutedwith ethyl acetate and extracted with aqueous Na₂CO₃. The organic phasewas collected and the aqueous phase was back-extracted with ethylacetate. The organic phases were combined, dried over Na₂SO₄ andevaporated down to dryness. The crude material was purified by flashchromatography (SiO₂, 5 g, ethyl acetate/heptane). MS (ESI, m/z): 351.6(MH+).

Example 1202-tert-butyl-5-[5-cyclopropyl-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridin-2-yl]-1,3,4-oxadiazole

The title compound was synthesized in a similar manner to Example 98,using the corresponding nitrile5-cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carbonitrilegenerated from (S)-1,1,1-Trifluoropropan-2-ol (CAS 3539-97-7) accordingto example 7a-d. MS (ESI, m/z): 356.6 (MH+).

Example 1213-tert-butyl-5-(5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 51c, using5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)picolinic acid from example98b. MS (ESI, m/z): 344.5 (MH+).

Example 1223-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazolea) tert-butyl(2S)-2-[[2-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-5-cyclopropylpyridin-4-yl]oxymethyl]pyrrolidine-1-carboxylate

The title compound was synthesized in analogy to Example 51d usingBoc-L-prolinol (CAS 69610-40-8). MS (ESI, m/z): 443.7 (MH+).

b)3-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-pyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole

tert-butyl(2S)-2-[[2-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-5-cyclopropylpyridin-4-yl]oxymethyl]pyrrolidine-1-carboxylate(364 mg, 823 μmol, Eq: 1.00) was dissolved in a 4M solution ofhydrochloric acid in 1,4-dioxane (19.5 ml, 78.1 mmol, Eq: 95) and thenstirred at rt for 1.5 hours and monitored by LC-MS. The solvent wasevaporated and the reaction mixture was diluted with ethyl acetate andwashed with NaHCO₃ and the organic phase was collected, dried overNa₂SO₄ and evaporated. The crude material was purified by flashchromatography (SiO₂, 20 g, ethyl acetate/heptane) to afford 104 mg ofthe title compound as a light yellow powder (Yield 37%). MS (ESI, m/z):343.6 (MH+).

c)3-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole

To a solution of3-tert-butyl-5-[5-cyclopropyl-4-[[(2S)-pyrrolidin-2-yl]methoxy]pyridin-2-yl]-1,2,4-oxadiazole(95 mg, 277 μmol, Eq: 1.00) and formaldehyde (295 mg, 360 μL, 3.63 mmol,Eq: 13.1) in dichloromethane (1.8 mL) was added sodiumtriacetoxyborohydride (300 mg, 1.42 mmol, Eq: 5.1). The reaction wasstirred 3 hours at rt, and monitored by LC-MS. The mixture was dilutedwith dichloromethane and washed with 1 N NaOH. The organic phase wasdried over Na₂SO₄ and evaporated. The crude material was purified byflash chromatography (SiO₂, 10 g, ethyl acetate/heptane) to afford 54 mgof the title compound as light yellow oil (Yield 54%). MS (ESI, m/z):357.6 (MH+).

Example 1233-tert-butyl-5-(5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazolea) 5-cyclopropyl-4-(2,2-difluoroethoxy)picolinic Acid

5-cyclopropyl-4-(2,2-difluoroethoxy)picolinonitrile (350 mg, 1.56 mmol,Eq: 1.00, previously described as Example 115a, was dissolved in aqueousHCl 25% (16.8 g, 15 ml, 115 mmol, Eq: 73.8). Reaction was heated at 110°C. for 1 hour and then cooled down to rt. HCl was neutralized using 6MNaOH aq. sol. Then pH adjusted to 1-2 with HCl 2M. The precipitateformed was then filtered. The remaining salt was precipitated withethanol and filtered giving the title compound as a light yellow solid.MS (ESI, m/z): 244.3 (MH+).

b)3-tert-butyl-5-(5-cyclopropyl-4-(2,2-difluoroethoxy)pyridin-2-yl)-1,2,4-oxadiazole

The title compound was synthesized in analogy to Example 51c, using5-cyclopropyl-4-(2,2-difluoroethoxy)picolinic acid. MS (ESI, m/z): 324.6(MH+).

Example 124 Pharmacological Tests

The following tests were carried out in order to determine the activityof the compounds of formula I:

Radioligand Binding Assay

The affinity of the compounds of the invention for cannabinoid CB1receptors was determined using recommended amounts of membranepreparations (PerkinElmer) of human embryonic kidney (HEK) cellsexpressing the human CNR1 or CNR2 receptors in conjunction with 1.5 or2.6 nM [3H]-CP-55,940 (Perkin Elmer) as radioligand, respectively.Binding was performed in binding buffer (50 mM Tris, 5 mM MgCl2, 2.5 mMEDTA, and 0.5% (wt/vol) fatty acid free BSA, pH 7.4 for CB1 receptor and50 mM Tris, 5 mM MgCl₂, 2.5 mM EGTA, and 0.1% (wt/vol) fatty acid freeBSA, pH 7.4 for CB2 receptor) in a total volume of 0.2 ml for 1 h at 30°C. shaking. The reaction was terminated by rapid filtration throughmicrofiltration plates coated with 0.5% polyethylenimine (UniFilter GF/Bfilter plate; Packard). Bound radioactivity was analyzed for Ki usingnonlinear regression analysis (Activity Base, ID Business Solution,Limited), with the Kd values for [3H]CP55,940 determined from saturationexperiments. The compounds of formula (I) show an excellent affinity forthe CB2 receptor with affinities below 10 μM, more particularly of 1 nMto 3 μM and most particularly of 1 nM to 100 nM.

cAMP Assay

CHO cells expressing human CB1 or CB2 receptors are seeded 17-24 hoursprior to the experiment 50.000 cells per well in a black 96 well platewith flat clear bottom (Corning Costar #3904) in DMEM (Invitrogen No.31331), 1×HT supplement, with 10% fetal calf serum and incubated at 5%CO₂ and 37° C. in a humidified incubator. The growth medium wasexchanged with Krebs Ringer Bicarbonate buffer with 1 mM IBMX andincubated at 30° C. for 30 min. Compounds were added to a final assayvolume of 100 μl and incubated for 30 min at 30° C. Using thecAMP-Nano-TRF detection kit the assay (Roche Diagnostics) was stopped bythe addition of 50 μl lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5%NP40, 10% NaN₃) and 50 μl detection solutions (20 μM mAb Alexa700-cAMP1:1, and 48 μM Ruthenium-2-AHA-cAMP) and shaken for 2 h at roomtemperature. The time-resolved energy transfer is measured by a TRFreader (Evotec Technologies GmbH), equipped with a ND:YAG laser asexcitation source. The plate is measured twice with the excitation at355 nm and at the emission with a delay of 100 ns and a gate of 100 ns,total exposure time 10 s at 730 (bandwidth 30 nm) or 645 nm (bandwidth75 nm), respectively. The FRET signal is calculated as follows:FRET=T730-Alexa730-P(T645-B645) with P=Ru730-B730/Ru645-B645, where T730is the test well measured at 730 nM, T645 is the test well measured at645 nm, B730 and B645 are the buffer controls at 730 nm and 645 nm,respectively. cAMP content is determined from the function of a standardcurve spanning from 10 μM to 0.13 nM cAMP.

EC₅₀ values were determined using Activity Base analysis (ID BusinessSolution, Limited). The EC₅₀ values for a wide range of cannabinoidagonists generated from this assay were in agreement with the valuespublished in the scientific literature.

The compounds of the invention are CB2 agonists with EC₅₀ below 0.5 μMand selectivity versus CB1 in the corresponding assay of at least 10fold. Particular compound of the invention are CB2 agonists with EC₅₀below 0.05 μM and selectivity versus CB1 in the corresponding assay ofat least 500 fold.

For example, the following compounds showed the following human EC₅₀values in the functional cAMP assay described above (in μM):

EC50 EC50 Example CB2 human CB1 human 1 0.0257 >10 2 0.0231 >10 30.0012 >10 4 0.0021 >10 5 0.0691 >10 6 0.001 0.0092 7 0.0111 >10 80.0213 >10 9 0.0158 >10 10 0.0008 >10 11 0.0006 >10 12 0.0466 >10 130.0319 >10 14 0.0037 >10 15 0.0198 >10 16 0.3426 >10 17 0.0205 >10 180.1104 >10 19 0.0137 >10 20 0.0037 >10 21 0.07 >10 22 0.0042 3.67542 230.0352 >10 24 0.0043 0.58087 25 0.135 >10 26 0.0308 >10 27 0.0035 >10 280.016 >10 29 0.7967 >10 30 0.0026 >10 31 0.0194 >10 32 0.0086 >10 330.0069 >10 34 0.0147 >10 35 0.0328 >10 36 0.0209 >10 37 0.2359 >10 380.1283 >10 39 0.4344 >10 40 0.0022 >10 41 0.0539 >10 42 0.0023 >10 430.0409 >10 44 0.0159 >10 45 0.0778 >10 46 0.1798 >10 47 0.1659 >10 480.019 >10 49 0.0515 >10 50 0.0458 >10 51 0.0618 >10 52 0.0131 >10 530.0014 0.05506 54 0.0331 >10 55 0.0077 >10 56 0.0447 >10 57 0.0134 >1058 0.0156 >10 59 0.0481 >10 60 0.4476 >10 61 0.0062 >10 62 0.0178 >10 630.0043 >10 64 0.0875 >10 65 0.0017 0.17031 66 0.009 >10 67 0.4343 >10 680.0726 >10 69 0.009 >10 70 0.0057 >10 71 0.2795 >10 72 0.0454 >10 730.0572 >10 74 0.0047 >10 75 0.2877 >10 76 0.0193 >10 77 0.0021 >10 780.0422 >10 79 0.009 >10 80 0.0475 >10 81 0.0211 >10 82 0.0379 >10 830.0301 >10 84 0.0501 >10 85 0.0356 1.33751 86 0.0482 1.40191 870.1127 >10 88 0.0529 >10 89 0.0162 >10 90 0.0118 >10 91 0.6412 >10 920.0751 0.76771 93 0.0119 0.23504 94 0.0602 >10 95 0.0261 >10 96 0.07591.01189 97 0.019 >10 98 0.042 >10 99 0.3174 >10 100 0.5179 >10 1010.1423 >10 102 0.0718 >10 103 0.0289 >10 104 0.0698 >10 105 0.0291 >10106 0.1279 >10 107 0.0958 >10 108 0.0698 >10 109 0.162 >10 110 0.103 >10111 0.0576 >10 112 0.0048 0.07317 113 0.0225 >10 114 0.0037 0.45539 1150.002 >10 116 0.0155 >10 117 0.0539 >10 118 0.035 >10 119 0.047 >10 1200.063 >10 121 0.001 >10 122 0.146 >10 123 0.002 >10

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mgMicrocrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg FilmCoat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mgTitan dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is then mixed with sodiumstarch glycolate and magnesium stearate and compressed to yield kernelsof 120 or 350 mg respectively. The kernels are lacquered with an aq.solution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mgMaize starch 20.0 mg Talc 5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Aceticacid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene glycol400 and water for injection (part). The pH is adjusted to 5.0 byaddition of acetic acid. The volume is adjusted to 1.0 ml by addition ofthe residual amount of water. The solution is filtered, filled intovials using an appropriate overage and sterilized.

1-14. (canceled)
 15. A compound selected from the group consisting of:3-cyclopropyl-5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-methyl-1,2,4-oxadiazole;3-tert-butyl-5-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;(4S)-4-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4,5-dihydro-1,3-oxazole;2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-4-ethyl-4,5-dihydro-1,3-oxazole;2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-ene;2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole;3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole;5-(azetidin-3-yl)-3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazole;2-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole;2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-3-oxa-1-azaspiro[4.5]dec-1-ene;5-tert-butyl-3-[4-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole;1-[6-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-4-(cyclopropylmethoxy)pyridin-3-yl]-6-oxa-1-azaspiro[3.3]heptane;3-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole;2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5,5-dimethyl-4H-1,3-oxazole;5-tert-butyl-3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazole;3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-propan-2-yl-1,2,4-oxadiazole;1-[3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]cyclopropan-1-ol;3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(3-methyloxetan-3-yl)-1,2,4-oxadiazole;3-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5-(1-methylcyclopropyl)-1,2,4-oxadiazole;5-tert-butyl-3-[5-cyclopropyl-4-(oxetan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;5-tert-butyl-3-[5-cyclopropyl-4-(1-methylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole3-[3-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-yl]oxetan-3-amine;5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;5-tert-butyl-3-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;2-(5-tert-butyl-1H-imidazol-2-yl)-5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine;5-tert-butyl-2-[5-cyclopropyl-4-(cyclopropylmethoxy)pyridin-2-yl]-1,3-oxazole;2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-propan-2-yl-1H-imidazol-5-one;2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-ethyl-4-methyl-1H-imidazol-5-one;2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-(2-methylpropyl)-1H-imidazol-5-one;2-[5-bromo-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-4-propan-2-yl-1H-imidazol-5-one;1-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]pyrrolidin-3-ol;5-tert-butyl-3-[5-cyclopropyl-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole;7-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]-2-oxa-7-azaspiro[3.4]octane;5-tert-butyl-3-[5-cyclopropyl-4-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole;4-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]morpholine;5-tert-butyl-3-(5-cyclopropyl-4-pyrrolidin-1-ylpyridin-2-yl)-1,2,4-oxadiazole;5-tert-butyl-3-[5-cyclopropyl-4-(3-methoxyazetidin-1-yl)pyridin-2-yl]-1,2,4-oxadiazole;6-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]-2-oxa-6-azaspiro[3.3]heptane;5-tert-butyl-3-[5-cyclopropyl-4-(oxan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;5-tert-butyl-3-[5-cyclopropyl-4-(1-ethylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole;5-tert-butyl-3-[5-cyclopropyl-4-(1-propan-2-ylpyrrolidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole;2-tert-butyl-5-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,3,4-oxadiazole;5-tert-butyl-3-[5-cyclopropyl-4-(1-methylpiperidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole;5-tert-butyl-3-[5-cyclopropyl-4-(1-ethylpiperidin-3-yl)oxypyridin-2-yl]-1,2,4-oxadiazole;5-tert-butyl-3-(5-cyclopropyl-4-piperidin-3-yloxypyridin-2-yl)-1,2,4-oxadiazole;5-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;5-tert-butyl-3-[5-(3-fluorooxetan-3-yl)-4-(4-fluorophenoxy)pyridin-2-yl]-1,2,4-oxadiazole;3-[2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4-methyl-5H-1,3-oxazol-4-yl]-5-methyl-1,2,4-oxadiazole;and5-tert-butyl-3-[6-chloro-5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;3-tert-butyl-5-(5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)-1,2,4-oxadiazole;or a pharmaceutically acceptable salt thereof.
 16. A compound selectedfrom the group consisting of:5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;5-tert-butyl-3-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole;and3-tert-butyl-5-(5-cyclopropyl-4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)-1,2,4-oxadiazole;or a pharmaceutically acceptable salt thereof. 17-19. (canceled)
 20. Apharmaceutical composition comprising a compound of claim 15, or apharmaceutically acceptable salt thereof, and a therapeutically inertcarrier. 21-25. (canceled)
 26. A pharmaceutical composition comprising acompound of claim 16, or a pharmaceutically acceptable salt thereof, anda therapeutically inert carrier.
 27. A compound of claim 15, wherein thecompound is2-[5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-4,4-diethyl-5H-1,3-oxazole,or a pharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition comprising a compound of claim 27, or a pharmaceuticallyacceptable salt thereof, and a therapeutically inert carrier.
 29. Acompound of claim 15, wherein the compound is2-[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5,5-dimethyl-4H-1,3-oxazole,or a pharmaceutically acceptable salt thereof.
 30. A pharmaceuticalcomposition comprising a compound of claim 29, or a pharmaceuticallyacceptable salt thereof, and a therapeutically inert carrier.
 31. Acompound of claim 15, wherein the compound is5-tert-butyl-3-[5-cyclopropyl-4-(oxolan-3-yloxy)pyridin-2-yl]-1,2,4-oxadiazole,or a pharmaceutically acceptable salt thereof.
 32. A pharmaceuticalcomposition comprising a compound of claim 31, or a pharmaceuticallyacceptable salt thereof, and a therapeutically inert carrier.
 33. Acompound of claim 15, wherein the compound is5-tert-butyl-3-[5-cyclopropyl-4-(oxan-4-yloxy)pyridin-2-yl]-1,2,4-oxadiazole,or a pharmaceutically acceptable salt thereof.
 34. A pharmaceuticalcomposition comprising a compound of claim 33, or a pharmaceuticallyacceptable salt thereof, and a therapeutically inert carrier.